Substituted eneoxindoles and uses thereof

ABSTRACT

The present disclosure relates generally to certain ene-oxindole compounds, pharmaceutical compositions comprising thereof. Also disclosed are methods of making and using said compounds and pharmaceutical compositions. The compounds and compositions disclosed herein may be used for the treatment or prevention of diseases, disorders, or infections modifiable by hematopoietic progenitor kinase 1 (HPK1) inhibitors, such as HBV, HIV, cancer, and/or a hyper-proliferative disease.

This application claims priority to U.S. Provisional Application No.62/851,875, filed May 23, 2019, which is incorporated herein in itsentirety for all purposes.

FIELD

This disclosure relates generally to certain eneoxindole compounds,pharmaceutical compositions comprising said compounds, and methods ofmaking and using said compounds and pharmaceutical compositions.

BACKGROUND

Immuno-oncology is an active area of cancer research, highlighted byinhibitor antibodies against the immune checkpoint receptors CTLA4, PD-1and PD-L1. Targeted disruption of these checkpoint pathways releases theimmune cell from key regulatory pathways, promoting an increase inimmune responses against cancer cells. Current therapies utilizing thesecheckpoint inhibitors are highlighted by significant and durableresponses to many different cancers. Unfortunately, these responses areoften coupled to low overall response rates across patient populations(<25%). Improving these response rates is a formidable goal, and thecombination of checkpoint blockade with other immune activating agentsor cell based therapies could provide a useful tool for expandingpatient responses.

Hematopoietic progenitor kinase 1 (HPK1), a STE20 ser/thr kinase fromthe germinal center family of kinases, regulates the function of diverseimmune populations including T cells, B cells, and dendritic cells (Huet al., Gens Dev, 1996; Alzabin et al., J Immunol 2009). In T cells,HPK1 negatively regulates T cell receptor (TCR) signaling (Liou et al.,Immunity 2000; Sauer et al., JBC 2001) by phosphorylating SLP76 onserine 376. Association of SLP76 with 14-3-3 protein subsequently leadsto the disassociation of the signaling complex (Di Bartolo et al., JEM2007). Further supporting the role of HPK1 as a negative regulator ofTCR signaling, murine HPK1 deficient T cells or HPK1 kinase inactivemutant T cells have enhanced ERK 1/2 activation and effector cytokinesecretion upon TCR activation compared to their wild-type counterparts(Shui et al., Nat Immunol 2007; Hernandez et al., Cell Reports 2018).Accordingly, a small molecule inhibitor of HPK1 could offer a method forincreasing the response to checkpoint receptor blockade therapy.

SUMMARY

Disclosed herein are compounds of Formula I:

or pharmaceutically acceptable salts thereof, wherein:

-   -   A is N or CR¹;    -   each R¹, R², and R³ is independently H, halogen, —CN, —N(R¹³)₂,        C₁-C₃ alkyl, C₁-C₃ haloalkyl, C₂-C₃ alkynyl, C₁-C₃ alkoxy, or        —SO₂R¹³, wherein the C₂-C₃ alkynyl is unsubstituted or        substituted with 1, 2, or 3 R⁹ groups;    -   one of B and E is

and the other is J;

-   -   J is H, —CN, C₁-C₃ alkyl, or C₃-C₆ cycloalkyl; wherein the C₁-C₃        alkyl or C₃-C₆ cycloalkyl is unsubstituted or substituted with        1, 2, or 3 R¹⁰ groups;

is a group of formula

wherein

-   -   W is NR⁴ or S;    -   X is N or CR;    -   Y is N or CR⁶;    -   Z is N or CR⁷;    -   X¹ is NH;    -   R⁴ is H;    -   each R⁵, R⁶, and R⁷ is independently H, halogen, —CN, —CON(R⁸)₂,        —NR¹³C(O)R¹³, —SO₂N(R¹³)₂, C₁-C₃ alkyl, C₁-C₃ alkoxy, —N(R¹³)₂,        C₃-C₆ cycloalkyl, C₆-C₁₀ aryl, 5-10 membered heteroaryl having        1, 2, or 3 heteroatoms independently selected from N, O, and S,        and 4-6 membered heterocyclyl having 1, 2, or 3 heteroatoms        independently selected from N, O, and S; wherein the C₁-C₃        alkyl, C₁-C₃ alkoxy, C₃-C₆ cycloalkyl, C₆-C₁₀ aryl, 5-10        membered heteroaryl, or 4-6 membered heterocyclyl is        unsubstituted or substituted with 1, 2, or 3 R¹¹ groups;    -   or wherein R⁵ and R⁶ or R⁶ and R⁷ together with atoms to which        they are attached form a phenyl or a 5-6 membered heteroaryl        having 1 or 2 heteroatoms independently selected from N, O, and        S; wherein the phenyl or the 5-6 membered heteroaryl is        unsubstituted or substituted with 1, 2, or 3 R¹¹ groups;    -   each R⁸ is independently H or C₁-C₃ alkyl, wherein the C₁-C₃        alkyl is unsubstituted or substituted with 1, 2, or 3 R¹²        groups; or    -   wherein two R⁸ groups together with the nitrogen they are        attached to form a 4-6 membered heterocyclic ring having 1 or 2        heteroatoms selected from the group consisting of N, O, or S,        wherein the 4-6 membered heterocyclic ring is unsubstituted or        substituted with 1, 2, or 3 R¹² groups;    -   each R⁹ is independently —OR¹³, C₁-C₃ alkyl, or C₃-C₆        cycloalkyl;    -   each R¹⁰ and R¹¹ is independently selected from the group        consisting of —OR¹³, halogen, CN, —N(R⁸)₂, —CON(R⁸)₂,        —N(R¹³)COR¹³, —S(O)₂R¹³, C₁-C₃ alkyl, C₃-C₆ cycloalkyl, 4-6        membered heterocyclyl having 1, 2, or 3 heteroatoms        independently selected from N, O, and S, C₆-C₁₀ aryl, and 5-10        membered heteroaryl having 1, 2, or 3 heteroatoms independently        selected from N, O, and S;    -   each R¹² is independently —OR¹³, C₁-C₃ alkyl, or —N(R¹³)₂;        wherein the C₁-C₃ alkyl is unsubstituted or substituted with 1,        2, or 3 groups independently selected from —OR¹³ and —N(R¹³)₂;    -   each R¹³ is independently H or C₁-C₃ alkyl, wherein the C₁-C₃        alkyl is unsubstituted or substituted with 1, 2, or 3 R²²        groups;    -   each R²² is independently selected from the group consisting of        halogen, —OH, C₁-C₃ alkyl, C₁-C₃ alkoxy, —NH₂, —NH(C₁-C₃ alkyl),        —N(C₁-C₃ alkyl)₂ wherein each C₁-C₃ alkyl is same or different,        C₃-C₆ cycloalkyl, 4-6 membered heterocyclyl with 1, 2, or 3        heteroatoms selected from N, O, and S, C₆-C₁₀ aryl, and 5-10        membered heteroaryl having 1, 2, or 3 heteroatoms independently        selected from N, O, and S; and

is a group of formula:

-   -   wherein L¹ is N or CR¹⁹;    -   n is 0, 1 or 2;    -   m is 0, 1, or 2;    -   p is 0, 1, 2, 3, 4, 5, or 6;

R¹⁹ is H, —OR¹³, halogen, CN, —N(R¹³)₂, or C₁-C₃ alkyl;

-   -   each R²⁰ is independently —OR¹³, halogen, CN, —N(R¹³)₂, or C₁-C₃        alkyl; and    -   each R²¹ is independently —OR¹³, oxo, halogen, CN, —N(R¹³)₂, or        C₁-C₃ alkyl;    -   or two R²¹ groups on same or adjoining atoms are joined together        to form a 3-6 membered carbocyclic ring or a 3-6 membered        heterocyclic ring having 1 or 2 heteroatoms selected from N, O,        and S.

In some embodiments, the compound of Formula I is of a Formula I-Z:

In some embodiments, the compound of Formula I is of a Formula I-E:

In some embodiments, the compound of Formula I and I-Z is of a FormulaII-Z:

In some embodiments, the compound of Formula I, I-Z, or II-Z is of aFormula IIa-Z:

In some embodiments, the compound of Formula I, I-Z, II-Z, and IIa-Z isa compound of Formula IIb-Z:

wherein L is N or CR¹⁵; M is N or CR¹⁶; Q is N or CR⁷; and R is N orCR¹⁸; and each R¹⁵, R¹⁶, R¹⁷, and R¹⁸ is independently selected from thegroup consisting of H, halogen, CN, —N(R⁸)₂, —CON(R⁸)₂, —N(R¹³)COR¹³,—S(O)₂R¹³, C₁-C₃ alkyl, C₁-C₃ alkoxy, C₆-C₁₀ aryl, 5-10 memberedheteroaryl having 1, 2, or 3 heteroatoms independently selected from N,O, and S, and 4-6 membered heterocyclyl having 1, 2, or 3 heteroatomsindependently selected from N, O, and S.

In some embodiments, the compound of Formula I or I-Z is of FormulaIII-Z:

In some embodiments, the compound of Formula I, I-Z or III-Z is of aFormula IIIa-Z:

wherein L is N or CR¹⁵; M is N or CR¹⁶; Q is N or CR¹⁷; and R is N orCR¹⁸; and each R¹⁵, R¹⁶, R¹⁷, and R¹⁸ is independently selected from thegroup consisting of H, halogen, CN, —N(R⁸)₂, —CON(R⁸)₂, —N(R¹³)COR¹³,—S(O)₂R¹³, C₁-C₃ alkyl, C₁-C₃ alkoxy, C₆-C₁₀ aryl, 5-10 memberedheteroaryl having 1, 2, or 3 heteroatoms independently selected from N,O, and S, and 4-6 membered heterocyclyl having 1, 2, or 3 heteroatomsindependently selected from N, O, and S.

Also provided are pharmaceutical compositions comprising a compounddisclosed herein, or the pharmaceutically acceptable salt thereof, and apharmaceutically acceptable excipient or carrier. In some embodiments,the pharmaceutical composition further comprises one or more additionaltherapeutic agents, or a pharmaceutically acceptable salt thereof.

Also provided are methods of inhibiting hematopoietic progenitor kinase1 (HPK1) activity in a subject in need thereof, wherein the methodscomprise administering to the subject a therapeutically effective amountof a compound of the disclosure, or the pharmaceutically acceptable saltthereof, or the pharmaceutical composition thereof.

Also provided are methods of treating a disease or disorder associatedwith increased hematopoietic progenitor kinase 1 (HPK1) activity in asubject in need thereof, wherein the methods comprise administering tothe subject a therapeutically effective amount of a compound disclosedherein, or the pharmaceutically acceptable salt thereof, or thepharmaceutical composition thereof.

Also provided are methods of increasing T-cell activation in a subjectin need thereof, the methods comprising administering to the subject atherapeutically effective amount of a compound of disclosed herein, orthe pharmaceutically acceptable salt thereof, or the pharmaceuticalcomposition thereof.

Also provided are methods of treating cancer in a subject in needthereof, comprising administering to the subject a therapeuticallyeffective amount of a compound disclosed herein, or the pharmaceuticallyacceptable salt thereof, or the pharmaceutical composition thereof. Insome embodiments, the cancer is selected from the group consisting ofbladder cancer, breast cancer, colorectal cancer, gastric cancer, headand neck squamous cell carcinoma, Hodgkin lymphoma, Merkel-cellcarcinoma, mesothelioma, melanoma, non-small cell lung cancer, lungcancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cellcarcinoma, small cell lung cancer, transitional cell carcinoma, andurothelial cancer.

Also provided are methods of inhibiting the growth or proliferation ofcancer cells in a subject in need thereof, wherein the methods compriseadministering to the subject a therapeutically effective amount of acompound disclosed herein, or the pharmaceutically acceptable saltthereof, or the pharmaceutical composition thereof.

Also provided are methods of treating or preventing a hepatitis B virus(HBV) infection in a subject in need thereof, wherein the methodscomprise administering to the subject a therapeutically effective amountof a compound disclosed herein, or the pharmaceutically acceptable saltthereof, or the pharmaceutical composition thereof.

Also provided are methods of treating or preventing a humanimmunodeficiency virus (HIV) infection in a subject in need thereof,wherein the methods comprise administering to the subject atherapeutically effective amount of a compound disclosed herein, or thepharmaceutically acceptable salt thereof, or the pharmaceuticalcomposition there.

In various embodiments, the methods of disclosed herein, furthercomprise administering a therapeutically effective amount of one or moreadditional therapeutic agents, or a pharmaceutically acceptable saltthereof.

Also provided are the use of the compounds disclosed herein in atherapy. In some embodiments, the compounds of the disclosure are foruse in a method of inhibiting hematopoietic progenitor kinase 1 (HPK1)activity in a subject in need thereof. In some embodiments, thecompounds provided herein are for use in a method of treating a diseaseor disorder associated with increased hematopoietic progenitor kinase 1(HPK1) activity in a subject in need thereof. In some embodiments, thecompounds provided herein are for use in a method of increasing T-cellactivation in a subject in need thereof. In some embodiments, thecompounds provided herein are for use in a method of treating cancer ina subject in need thereof. In some embodiments, the compounds providedherein are for use in a method of inhibiting the growth or proliferationof cancer cells in a subject in need thereof. In some embodiments, thecompounds provided herein are for use in a method of treating orpreventing a hepatitis B virus (HBV) infection in a subject in needthereof. In some embodiments, the compounds provided herein are for usein a method of treating or preventing a human immunodeficiency virus(HIV) infection in a subject in need thereof.

In some embodiments, the compounds disclosed herein are used with one ormore additional therapeutic agents, or a pharmaceutically acceptablesalt thereof.

DETAILED DESCRIPTION I. Definitions

The description below is made with the understanding that the presentdisclosure is to be considered as an exemplification of the claimedsubject matter, and is not intended to limit the appended claims to thespecific embodiments illustrated. The headings used throughout thisdisclosure are provided for convenience and are not to be construed tolimit the claims in any way. Embodiments illustrated under any headingmay be combined with embodiments illustrated under any other heading.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art. It must be noted that as used herein and in the appendedclaims, the singular forms “a”, “and”, and “the” include pluralreferents unless the context clearly dictates otherwise. Thus, e.g.,reference to “the compound” includes a plurality of such compounds andreference to “the assay” includes reference to one or more assays andequivalents thereof known to those skilled in the art, and so forth.

As used in the present disclosure, the following words, phrases andsymbols are generally intended to have the meanings as set forth below,except to the extent that the context in which they are used indicatesotherwise.

A dash (“-”) that is not between two letters or symbols is used toindicate a point of attachment for a substituent. For example, —CONH₂ isattached through the carbon atom. A dash at the front or end of achemical group is a matter of convenience; chemical groups may bedepicted with or without one or more dashes without losing theirordinary meaning. A wavy line drawn through a line in a structureindicates a point of attachment of a group. Unless chemically orstructurally required, no directionality is indicated or implied by theorder in which a chemical group is written or named. A solid line comingout of the center of a ring indicates that the point of attachment for asubstituent on the ring can be at any ring atom. For example, R^(a) inthe below structure can be attached to any of the five carbon ring atomsor R^(a) can replace the hydrogen attached to the nitrogen ring atom:

The prefix “C_(u-v)” and/or “C_(u)-C_(v)” indicates that the followinggroup has from u to v carbon atoms. For example, “C₁₋₆ alkyl” and/or“C₁-C₆ alkyl” indicates that the alkyl group has from 1 to 6 carbonatoms. Likewise, the term “x-y membered” rings, wherein x and y arenumerical ranges, such as “3-12-membered heterocyclyl”, refers to a ringcontaining x-y atoms (e.g. 3-12), of which up to 80% may be heteroatoms,such as N, O, S, P, and the remaining atoms are carbon.

Also, certain commonly used alternative chemical names may or may not beused. For example, a divalent group such as a divalent “alkyl” group, adivalent “aryl” group, etc., may also be referred to as an “alkylene”group or an “alkylenyl” group, or alkylyl group, an “arylene” group oran “aiylenyl” group, or arylyl group, respectively.

“A compound disclosed herein” or “a compound of the present disclosure”or “a compound provided herein” or “a compound described herein” refersto the compounds of Formula I, II, IIa, IIb, III, or IIIa. Also includedare the specific compounds of Examples C1 to C70.

Reference to “about” a value or parameter herein includes (anddescribes) embodiments that are directed to that value or parameter perse. In certain embodiments, the term “about” includes the indicatedamount 10%. In other embodiments, the term “about” includes theindicated amount 5%. In certain other embodiments, the term “about”includes the indicated amount±1%. Also, the term “about X” includesdescription of “X”.

The term “adjoining atoms” as used herein refers to atoms that areimmediately next to each other. For example, in “C₁-C₂-C₃-C₄” atoms C₁and C₃ are adjoining atoms to C₂, atoms C₂ and C₄ are adjoining atoms toC₃, atom C₂ is adjoining atom to C₁, and atom C₃ is adjoining atom toC₄.

“Alkyl” refers to an unbranched or branched saturated hydrocarbon chain.As used herein, alkyl has 1 to 20 carbon atoms (i.e., C₁-C₂₀ alkyl), 1to 8 carbon atoms (i.e., C₁-C₈ alkyl), 1 to 6 carbon atoms (i.e., C₁-C₆alkyl), or 1 to 4 carbon atoms (i.e., C₁-C₄ alkyl). Examples of alkylgroups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl,iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl,2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having aspecific number of carbons is named by chemical name or identified bymolecular formula, all positional isomers having that number of carbonsmay be encompassed; thus, for example, “butyl” includes n-butyl (i.e.—(CH₂)₃CH₃), sec-butyl (i.e. —CH(CH₃)CH₂CH₃), isobutyl (i.e.—CH₂CH(CH₃)₂) and tert-butyl (i.e. —C(CH₃)₃); and “propyl” includesn-propyl (i.e. —(CH₂)₂CH₃) and isopropyl (i.e. —CH(CH₃)₂).

“Alkenyl” refers to an aliphatic group containing at least onecarbon-carbon double bond and having from 2 to 20 carbon atoms (i.e.,C₂-C₂₀ alkenyl), 2 to 8 carbon atoms (i.e., C₂-C₈ alkenyl), 2 to 6carbon atoms (i.e., C₂-C₆ alkenyl), or 2 to 4 carbon atoms (i.e., C₂-C₄alkenyl). Examples of alkenyl groups include ethenyl, propenyl,butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

“Alkynyl” refers to an aliphatic group containing at least onecarbon-carbon triple bond and having from 2 to 20 carbon atoms (i.e.,C₂-C₂₀ alkynyl), 2 to 8 carbon atoms (i.e., C₂-C₈ alkynyl), 2 to 6carbon atoms (i.e., C₂-C₆ alkynyl), or 2 to 4 carbon atoms (i.e., C₂-C₄alkynyl). The term “alkynyl” also includes those groups having onetriple bond and one double bond.

“Alkoxy” refers to the group “alkyl-O—”. Examples of alkoxy groupsinclude methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy,sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. “Haloalkoxy”refers to an alkoxy group as defined above, wherein one or more hydrogenatoms are replaced by a halogen.

“Acyl” refers to a group —C(═O)R, wherein R is hydrogen, alkyl,cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each ofwhich may be optionally substituted, as defined herein. Examples of acylinclude formyl, acetyl, cylcohexylcarbonyl, cyclohexylmethyl-carbonyl,and benzoyl.

“Amido” refers to both a “C-amido” group which refers to the group—C(═O)NRYR^(z) and an “N-amido” group which refers to the group—NRYC(═O)R^(z), wherein R and R are independently selected from thegroup consisting of hydrogen, alkyl, aryl, haloalkyl, heteroaryl,cycloalkyl, and heterocyclyl; each of which may be optionallysubstituted.

“Amino” refers to the group —NR^(y)R^(z) wherein R^(y) and R^(z) areindependently selected from the group consisting of hydrogen, alkyl,haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl; each of whichmay be optionally substituted.

“Aryl” refers to an aromatic carbocyclic group having a single ring(e.g. monocyclic) or multiple rings (e.g. bicyclic or tricyclic)including fused systems. As used herein, aryl has 6 to 20 ring carbonatoms (i.e., C₆-C₂₀ aryl), 6 to 12 carbon ring atoms (i.e., C₆-C₁₂aryl), or 6 to 10 carbon ring atoms (i.e., C₆-C₁₀ aryl). Examples ofaryl groups include phenyl, naphthyl, fluorenyl, and anthryl. Aryl,however, does not encompass or overlap in any way with heteroaryldefined below. If one or more aryl groups are fused with a heteroarylring, the resulting ring system is heteroaryl.

“Cyano” or “carbonitrile” refers to the group —CN.

“Cycloalkyl” refers to a saturated or partially saturated cyclic alkylgroup having a single ring or multiple rings including fused, bridged,and spiro ring systems. The term “cycloalkyl” includes cycloalkenylgroups (i.e. the cyclic group having at least one double bond). As usedherein, cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C₃-C₂₀cycloalkyl), 3 to 12 ring carbon atoms (i.e., C₃-C₁₂ cycloalkyl), 3 to10 ring carbon atoms (i.e., C₃-C₁₀ cycloalkyl), 3 to 8 ring carbon atoms(i.e., C₃-C₈ cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C₃-C₆cycloalkyl). Examples of cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, and cyclohexyl.

“Bridged” refers to a ring fusion wherein non-adjacent atoms on a ringare joined by a divalent substituent, such as alkylenyl group, analkylenyl group containing one or two heteroatoms, or a singleheteroatom. Quinuclidinyl and admantanyl are examples of bridged ringsystems.

The term “fused” refers to a ring which is bound to an adjacent ring.

“Spiro” refers to a ring substituent which is joined by two bonds at thesame carbon atom. Examples of spiro groups include1,1-diethylcyclopentane, dimethyl-dioxolane, and4-benzyl-4-methylpiperidine, wherein the cyclopentane and piperidine,respectively, are the spiro substituents.

“Halogen” or “halo” includes fluoro, chloro, bromo, and iodo.“Haloalkyl” refers to an unbranched or branched alkyl group as definedabove, wherein one or more hydrogen atoms are replaced by a halogen. Forexample, where a residue is substituted with more than one halogen, itmay be referred to by using a prefix corresponding to the number ofhalogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkylsubstituted with two (“di”) or three (“tri”) halo groups, which may be,but are not necessarily, the same halogen. Examples of haloalkyl includedifluoromethyl (—CHF₂) and trifluoromethyl (—CF₃).

“Heteroaryl” refers to an aromatic group having a single ring, multiplerings, or multiple fused rings, with one or more ring heteroatomsindependently selected from nitrogen, oxygen, and sulfur. As usedherein, heteroaryl includes 1 to 20 carbon ring atoms (i.e., C₁-C₂heteroaryl), 3 to 12 carbon ring atoms (i.e., C₃-C₁₂ heteroaryl), or 3to 8 carbon ring atoms (i.e., C₃-C₈ heteroaryl); and 1 to 5 ringheteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2ring heteroatoms, or 1 ring heteroatom independently selected fromnitrogen, oxygen, and sulfur. Examples of heteroaryl groups includepyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, andpyrazolyl. Heteroaryl does not encompass or overlap with aryl as definedabove.

“Heterocyclyl” or “heterocyclic ring” refers to a non-aromatic cyclicalkyl group, with one or more ring heteroatoms independently selectedfrom nitrogen, oxygen and sulfur. As used herein, “heterocyclyl” or“heterocyclic ring” refer to rings that are saturated or partiallysaturated unless otherwise indicated, e.g., in some embodiments“heterocyclyl” or “heterocyclic ring” refers to rings that are partiallysaturated where specified. The term “heterocyclyl” or “heterocyclicring” includes heterocycloalkenyl groups (i.e., the heterocyclyl grouphaving at least one double bond). A heterocyclyl may be a single ring ormultiple rings wherein the multiple rings may be fused, bridged, orspiro. As used herein, heterocyclyl has 2 to 20 carbon ring atoms (i.e.,C₂-C₂₀ heterocyclyl), 2 to 12 carbon ring atoms (i.e., C₂-C₁₂heterocyclyl), 2 to 10 carbon ring atoms (i.e., C₂-C₁₀ heterocyclyl), 2to 8 carbon ring atoms (i.e., C₂-C₈ heterocyclyl), 3 to 12 carbon ringatoms (i.e., C₃-C₁₂ heterocyclyl), 3 to 8 carbon ring atoms (i.e., C₃-C₈heterocyclyl), or 3 to 6 carbon ring atoms (i.e., C₃-C₆ heterocyclyl);having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ringheteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independentlyselected from nitrogen, sulfur or oxygen. Examples of heterocyclylgroups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl,dioxolanyl, azetidinyl, and morpholinyl. As used herein, the term“bridged-heterocyclyl” refers to a four- to ten-membered cyclic moietyconnected at two non-adjacent atoms of the heterocyclyl with one or more(e.g., 1 or 2) four- to ten-membered cyclic moiety having at least oneheteroatom where each heteroatom is independently selected fromnitrogen, oxygen, and sulfur. As used herein, “bridged-heterocyclyl”includes bicyclic and tricyclic ring systems. Also as used herein, theterm “spiro-heterocyclyl” refers to a ring system in which a three- toten-membered heterocyclyl has one or more additional ring, wherein theone or more additional ring is three- to ten-membered cycloalkyl orthree- to ten-membered heterocyclyl, where a single atom of the one ormore additional ring is also an atom of the three- to ten-memberedheterocyclyl. Examples of the spiro-heterocyclyl include bicyclic andtricyclic ring systems, such as 2-oxa-7-azaspiro[3.5]nonanyl,2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl. As usedherein, the terms “heterocyclyl”, and “heterocyclic ring” are usedinterchangeably. In some embodiments, a heterocyclyl is substituted withan oxo group.

“Hydroxy” or “hydroxyl” refers to the group —OH.

“Oxo” refers to the group (═O) or (O).

“Sulfonyl” refers to the group —S(O)₂R^(c), where R^(c) is alkyl,haloalkyl, heterocyclyl, cycloalkyl, heteroaryl, or aryl. Examples ofsulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, andtoluenesulfonyl.

Whenever the graphical representation of a group terminates in a singlybonded nitrogen atom, that group represents an —NH group unlessotherwise indicated. Similarly, unless otherwise expressed, hydrogenatom(s) are implied and deemed present where necessary in view of theknowledge of one of skill in the art to complete valency or providestability.

The terms “optional” or “optionally” mean that the subsequentlydescribed event or circumstance may or may not occur, and that thedescription includes instances where said event or circumstance occursand instances in which it does not. Also, the term “optionallysubstituted” means that any one or more hydrogen atoms on the designatedatom or group may or may not be replaced by a moiety other thanhydrogen.

The term “substituted” means that any one or more hydrogen atoms on thedesignated atom or group is replaced with one or more substituents otherthan hydrogen, provided that the designated atom's normal valence is notexceeded. The one or more substituents include, but are not limited to,alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl,azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo,haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino,imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl,thiocyanate, thiol, thione, or combinations thereof. Polymers or similarindefinite structures arrived at by defining substituents with furthersubstituents appended ad infinitum (e.g., a substituted aryl having asubstituted alkyl which is itself substituted with a substituted arylgroup, which is further substituted by a substituted heteroalkyl group,etc.) are not intended for inclusion herein. Unless otherwise noted, themaximum number of serial substitutions in compounds described herein isthree. For example, serial substitutions of substituted aryl groups withtwo other substituted aryl groups are limited to ((substitutedaryl)substituted aryl) substituted aryl. Similarly, the abovedefinitions are not intended to include impermissible substitutionpatterns (e.g., methyl substituted with 5 fluorines or heteroaryl groupshaving two adjacent oxygen ring atoms). Such impermissible substitutionpatterns are well known to the skilled artisan. When used to modify achemical group, the term “substituted” may describe other chemicalgroups defined herein. For example, the term “substituted aryl”includes, but is not limited to, “alkylaryl.” Unless specifiedotherwise, where a group is described as optionally substituted, anysubstituents of the group are themselves unsubstituted.

In some embodiments, the term “substituted alkyl” refers to an alkylgroup having one or more substituents including hydroxyl, halo, amino,alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In additionalembodiments, “substituted cycloalkyl” refers to a cycloalkyl grouphaving one or more substituents including alkyl, haloalkyl, cycloalkyl,heterocyclyl, aryl, heteroaryl, amino, alkoxy, halo, oxo, and hydroxyl;“substituted heterocyclyl” refers to a heterocyclyl group having one ormore substituents including alkyl, amino, haloalkyl, heterocyclyl,cycloalkyl, aryl, heteroaryl, alkoxy, halo, oxo, and hydroxyl;“substituted aryl” refers to an aryl group having one or moresubstituents including halo, alkyl, amino, haloalkyl, cycloalkyl,heterocyclyl, heteroaryl, alkoxy, and cyano; “substituted heteroaryl”refers to an heteroaryl group having one or more substituents includinghalo, amino, alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl,heteroaryl, alkoxy, and cyano and “substituted sulfonyl” refers to agroup —S(O)₂R, in which R is substituted with one or more substituentsincluding alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl. Inother embodiments, the one or more substituents may be furthersubstituted with halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl,heterocyclyl, aryl, or heteroaryl, each of which is substituted. Inother embodiments, the substituents may be further substituted withhalo, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclyl,aryl, or heteroaryl, each of which is unsubstituted.

In some embodiments, a substituted cycloalkyl, a substitutedheterocyclyl, a substituted aryl, and/or a substituted heteroarylincludes a cycloalkyl, a heterocyclyl, an aryl, and/or a heteroaryl thathas a substituent on the ring atom to which the cycloalkyl,heterocyclyl, aryl, and/or heteroaryl is attached to the rest of thecompound. For example, in the below moiety, the cyclopropyl issubstituted with a methyl group:

The compounds of the embodiments disclosed herein, or theirpharmaceutically acceptable salts may contain one or more asymmetriccenters and may thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids.The present disclosure is meant to include all such possible isomers, aswell as their racemic and optically pure forms. Optically active (+) and(−), (R)- and (S)-, or (D)- and (L)- isomers may be prepared usingchiral synthons or chiral reagents, or resolved using conventionaltechniques, for example, chromatography and fractional crystallization.Conventional techniques for the preparation/isolation of individualenantiomers include chiral synthesis from a suitable optically pureprecursor or resolution of the racemate (or the racemate of a salt orderivative) using, for example, chiral high pressure liquidchromatography (HPLC). When the compounds described herein containolefinic double bonds or other centers of geometric asymmetry, andunless specified otherwise, it is intended that the compounds includeboth E and Z geometric isomers. Likewise, all tautomeric forms are alsointended to be included. Where compounds are represented in their chiralform, it is understood that the embodiment encompasses, but is notlimited to, the specific diastereomerically or enantiomerically enrichedform. Where chirality is not specified but is present, it is understoodthat the embodiment is directed to either the specificdiastereomerically or enantiomerically enriched form; or a racemic orscalemic mixture of such compound(s). As used herein, “scalemic mixture”is a mixture of stereoisomers at a ratio other than 1:1.

A “stereoisomer” refers to a compound made up of the same atoms bondedby the same bonds but having different three-dimensional structures,which are not interchangeable. The present disclosure contemplatesvarious stereoisomers and mixtures thereof and includes “enantiomers”,which refers to two stereoisomers whose molecules are non-superimposablemirror images of one another.

“Enantiomers” are a pair of stereoisomers that are non-superimposablemirror images of each other. A 1:1 mixture of a pair of enantiomers is a“racemic” mixture. A mixture of enantiomers at a ratio other than 1:1 isa “scalemic” mixture.

“Diastereoisomers” are stereoisomers that have at least two asymmetricatoms, but which are not mirror-images of each other.

A “tautomer” refers to a proton shift from one atom of a molecule toanother atom of the same molecule. The present disclosure includestautomers of any compounds provided herein.

Some of the compounds provided herein exist as tautomeric isomers.Tautomeric isomers are in equilibrium with one another. For example,amide containing compounds may exist in equilibrium with imidic acidtautomers. Regardless of which tautomer is shown, and regardless of thenature of the equilibrium among tautomers, the compounds are understoodby one of ordinary skill in the art to comprise both amide and imidicacid tautomers. Thus, the amide containing compounds are understood toinclude their imidic acid tautomers. Likewise, the imidic acidcontaining compounds are understood to include their amide tautomers.

A “solvate” is formed by the interaction of a solvent and a compound.Solvates of salts of the compounds provided herein are also provided.Hydrates of the compounds provided herein are also provided.

Any formula or structure provided herein is also intended to representunlabeled forms as well as isotopically labeled forms of the compounds.Isotopically labeled compounds have structures depicted by the formulasgiven herein except that one or more atoms are replaced by an atomhaving a selected atomic mass or mass number. Examples of isotopes thatcan be incorporated into compounds of the disclosure include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine,such as, but not limited to ²H (deuterium, D), ³H (tritium), ¹¹C, ¹³C,¹⁴C, ¹⁵N, ¹⁸F, ³¹P, ³²P, ³⁵S, ³⁶C and ¹²⁵I. Various isotopically labeledcompounds of the present disclosure, for example those into whichradioactive isotopes such as ²H, ³H, ¹³C and ¹⁴C are incorporated, arealso provided herein. Such isotopically labelled compounds may be usefulin metabolic studies, reaction kinetic studies, detection or imagingtechniques, such as positron emission tomography (PET) or single-photonemission computed tomography (SPECT) including drug or substrate tissuedistribution assays or in radioactive treatment of patients.

The present disclosure also includes compounds of Formula I, I-Z, I-E,II-Z, IIa-Z, IIb-Z, III-Z, or IIIa-Z in which from 1 to n hydrogensattached to a carbon atom is/are replaced by deuterium, in which n isthe number of hydrogens in the molecule. Such compounds exhibitincreased resistance to metabolism and are thus useful for increasingthe half-life of any compound of Formula I, I-Z, I-E, II-Z, IIa-Z,IIb-Z, III-Z, or IIIa-Z, when administered to a mammal, particularly ahuman. See, for example, Foster, “Deuterium Isotope Effects in Studiesof Drug Metabolism,” Trends Pharmacol. Sci. 5(12):524-527 (1984). Suchcompounds are synthesized by means well known in the art, for example byemploying starting materials in which one or more hydrogens have beenreplaced by deuterium.

Deuterium labelled or substituted therapeutic compounds of the presentdisclosure may have improved DMPK (drug metabolism and pharmacokinetics)properties, relating to absorption, distribution, metabolism andexcretion (ADME). Substitution with heavier isotopes such as deuteriummay afford certain therapeutic advantages resulting from greatermetabolic stability, for example, increased in vivo half-life, reduceddosage requirements and/or an improvement in therapeutic index. An ¹⁸Flabeled compound may be useful for PET or SPECT studies. Isotopicallylabeled compounds of this disclosure and prodrugs thereof can generallybe prepared by carrying out the procedures disclosed in the schemes orin the examples and preparations described below by substituting areadily available isotopically labeled reagent for a non-isotopicallylabeled reagent. It is understood that deuterium in this context isregarded as a substituent in the compound of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, or IIIa-Z.

The concentration of such a heavier isotope, specifically deuterium, maybe defined by an isotopic enrichment factor. In the compounds of thisdisclosure, any atom not specifically designated as a particular isotopeis meant to represent any stable isotope of that atom. Unless otherwisestated, when a position is designated specifically as “H” or “hydrogen”,the position is understood to have hydrogen at its natural abundanceisotopic composition. Accordingly, in the compounds of this disclosure,any atom specifically designated as a deuterium (D) is meant torepresent deuterium.

In many cases, the compounds of this disclosure are capable of formingacid and/or base salts by virtue of the presence of amino and/orcarboxyl groups or groups similar thereto.

The term “pharmaceutically acceptable salt” of a given compound refersto salts that retain the biological effectiveness and properties of thegiven compound, and which are not biologically or otherwise undesirable.Pharmaceutically acceptable base addition salts can be prepared frominorganic and organic bases. Salts derived from inorganic bases include,by way of example only, sodium, potassium, lithium, ammonium, calciumand magnesium salts. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary and tertiary amines, such asalkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines,di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenylamines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines,di(substituted alkenyl) amines, tri(substituted alkenyl) amines, mono,di or tri cycloalkyl amines, mono, di or tri arylamines or mixed amines,and the like. Specific examples of suitable amines include, by way ofexample only, isopropylamine, trimethyl amine, diethyl amine,tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine,2-dimethylaminoethanol, piperazine, piperidine, morpholine,N-ethylpiperidine, and the like.

Pharmaceutically acceptable acid addition salts may be prepared frominorganic and organic acids. Salts derived from inorganic acids includehydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like. Salts derived from organic acids includeacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid,malic acid, malonic acid, succinic acid, maleic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid,salicylic acid, and the like.

As used herein, “pharmaceutically acceptable carrier” or“pharmaceutically acceptable excipient” includes any and all solvents,dispersion media, coatings, antibacterial and antifungal agents,isotonic and absorption delaying agents and the like. The use of suchmedia and agents for pharmaceutically active substances is well known inthe art. Except insofar as any conventional media or agent isincompatible with the active ingredient, its use in the therapeuticcompositions is contemplated. Supplementary active ingredients can alsobe incorporated into the compositions.

“Treatment” or “treating” is an approach for obtaining beneficial ordesired results including clinical results. Beneficial or desiredclinical results may include one or more of the following: a) inhibitingthe disease or condition (e.g., decreasing one or more symptomsresulting from the disease or condition, and/or diminishing the extentof the disease or condition); b) slowing or arresting the development ofone or more clinical symptoms associated with the disease or condition(e.g., stabilizing the disease or condition, preventing or delaying theworsening or progression of the disease or condition, and/or preventingor delaying the spread (e.g., metastasis) of the disease or condition);and/or c) relieving the disease, that is, causing the regression ofclinical symptoms (e.g., ameliorating the disease state, providingpartial or total remission of the disease or condition, enhancing effectof another medication, delaying the progression of the disease,increasing the quality of life, and/or prolonging survival.

“Prevention” or “preventing” means any treatment of a disease orcondition that causes the clinical symptoms of the disease or conditionnot to develop. Compounds may, in some embodiments, be administered to asubject (including a human) who is at risk or has a family history ofthe disease or condition.

“Subject” refers to an animal, such as a mammal (including a human),that has been or will be the object of treatment, observation orexperiment. The methods described herein may be useful in human therapyand/or veterinary applications. In some embodiments, the subject is amammal. In one embodiment, the subject is a human.

The term “therapeutically effective amount” or “effective amount” of acompound described herein or pharmaceutically acceptable salts, isomer,or a mixture thereof means an amount sufficient to effect treatment whenadministered to a subject, to provide a therapeutic benefit such asamelioration of symptoms or slowing of disease progression. For example,a therapeutically effective amount may be an amount sufficient todecrease a symptom of a disease or condition responsive to inhibition ofhematopoietic progenitor kinase 1 (HPK1) activity. The therapeuticallyeffective amount may vary depending on the subject, and the disease orcondition being treated, the weight and age of the subject, the severityof the disease or condition, and the manner of administering, which canreadily be determined by one of ordinary skill in the art.

The term “inhibition” indicates a decrease in the baseline activity of abiological activity or process. “Inhibition of activity of HPK1” orvariants thereof refers to a decrease in HPK1 activity as a direct orindirect response to the presence of a compound of the presentdisclosure relative to the HPK1 activity in the absence of the compoundof the present disclosure. “Inhibition of HPK1” refers to a decrease inHPK1 activity as a direct or indirect response to the presence of acompound provided herein relative to the HPK1 activity in the absence ofthe compound provided herein. In some embodiments, the inhibition ofHPK1 activity may be compared in the same subject prior to treatment, orother subjects not receiving the treatment.

II. Compounds

In one aspect, provided herein is a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   A is N or CR¹;    -   each R¹, R², and R³ is independently H, halogen, —CN, —N(R¹³)₂,        C₁-C₃ alkyl, C₁-C₃ haloalkyl, C₂-C₃ alkynyl, C₁-C₃ alkoxy, or        —SO₂R¹³, wherein the C₂-C₃ alkynyl is unsubstituted or        substituted with 1, 2, or 3 R⁹ groups;    -   one of B and E is

and the other is J;

-   -   J is H, —CN, C₁-C₃ alkyl, or C₃-C₆ cycloalkyl; wherein the C₁-C₃        alkyl or C₃-C₆ cycloalkyl is unsubstituted or substituted with        1, 2, or 3 R¹⁰ groups;

is a group of formula

wherein

-   -   W is NR⁴ or S;    -   X is N or CR;    -   Y is N or CR⁶;    -   Z is N or CR⁷;    -   X¹ is NH;    -   R⁴ is H;    -   each R⁵, R⁶, and R⁷ is independently H, halogen, —CN, —CON(R⁸)₂,        —NR¹³C(O)R¹³, —SO₂N(R¹³)₂, C₁-C₃ alkyl, C₁-C₃ alkoxy, —N(R¹³)₂,        C₃-C₆ cycloalkyl, C₆-C₁₀ aryl, 5-10 membered heteroaryl having        1, 2, or 3 heteroatoms independently selected from N, O, and S,        and 4-6 membered heterocyclyl having 1, 2, or 3 heteroatoms        independently selected from N, O, and S; wherein the C₁-C₃        alkyl, C₁-C₃ alkoxy, C₃-C₆ cycloalkyl, C₆-C₁₀ aryl, 5-10        membered heteroaryl, or 4-6 membered heterocyclyl is        unsubstituted or substituted with 1, 2, or 3 R¹¹ groups;    -   or wherein R⁵ and R⁶, or R⁶ and R⁷ together with atoms to which        they are attached form a phenyl or a 5-6 membered heteroaryl        having 1 or 2 heteroatoms independently selected from N, O, and        S, wherein the phenyl or the 5-6 membered heteroaryl is        unsubstituted or substituted with 1, 2, or 3 R¹¹ groups;    -   each R⁸ is independently H or C₁-C₃ alkyl, wherein the C₁-C₃        alkyl is unsubstituted or substituted with 1, 2, or 3 R¹²        groups; or wherein two R⁸ groups together with the nitrogen they        are attached to form a 4-6 membered heterocyclic ring having 1        or 2 heteroatoms selected from the group consisting of N, O, or        S, wherein the 4-6 membered heterocyclic ring is unsubstituted        or substituted with 1, 2, or 3 R¹² groups;    -   each R⁹ is independently —OR¹³, C₁-C₃ alkyl, or C₃-C₆        cycloalkyl;    -   each R¹⁰ and R¹¹ is independently selected from the group        consisting of —OR¹³, halogen, CN, —N(R⁸)₂, —CON(R⁸)₂,        —N(R¹³)COR¹³, —S(O)₂R¹³, C₁-C₃ alkyl, C₃-C₆ cycloalkyl, 4-6        membered heterocyclyl having 1, 2, or 3 heteroatoms        independently selected from N, O, and S, C₆-C₁₀ aryl, and 5-10        membered heteroaryl having 1, 2, or 3 heteroatoms independently        selected from N, O, and S;    -   each R¹² is independently —OR¹³, C₁-C₃ alkyl, or —N(R¹³)₂;        wherein the C₁-C₃ alkyl is unsubstituted or substituted with 1,        2, or 3 groups independently selected from —OR¹³ and —N(R¹³)₂;    -   each R¹³ is independently H or C₁-C₃ alkyl wherein the C₁-C₃        alkyl is unsubstituted or substituted with 1, 2, or 3 R²²        groups;    -   each R²² is independently selected from the group consisting of        halogen, —OH, C₁-C₃ alkyl, C₁-C₃ alkoxy, —NH₂, —NH(C₁-C₃ alkyl),        —N(C₁-C₃ alkyl)₂ wherein each C₁-C₃ alkyl is same or different,        C₃-C₆ cycloalkyl, a 4-6 membered heterocyclyl with 1, 2, or 3        heteroatoms selected from N, O, and S, C₆-C₁₀ aryl, and a 5-10        membered heteroaryl having 1, 2, or 3 heteroatoms independently        selected from N, O, and S; and

is a group of formula:

-   -   wherein L¹ is N or CR¹⁹;

-   -   n is 0, 1 or 2;    -   m is 0, 1, or 2;    -   p is 0, 1, 2, 3, 4, 5, or 6;    -   R¹⁹ is H, —OR¹³, halogen, CN, —N(R¹³)₂, or C₁-C₃ alkyl;    -   each R²⁰ is independently —OR¹³, halogen, CN, —N(R¹³)₂, or C₁-C₃        alkyl; and    -   each R²¹ is independently —OR¹³, oxo, halogen, CN, —N(R¹³)₂, or        C₁-C₃ alkyl;    -   or two R²¹ groups on same or adjoining atoms are joined together        to form a 3-6 membered carbocyclic ring or a 3-6 membered        heterocyclic ring having 1 or 2 heteroatoms selected from N, O,        and S.

In some embodiments, the compound of Formula I is of a Formula I-Z:

wherein the variables A, R², R³, J,

are as defined above for Formula I.

In some embodiments, the compound of Formula I is of Formula I-E:

wherein the variables A, R², R³, J,

are as defined above for Formula I.

In some embodiments, of the compounds of Formula I, I-Z, or I-E

wherein W is NH or S; X is N or CR⁵; Y is N or CR⁶; and Z is N or CR⁷;wherein each R⁵, R⁶, and R⁷ is independently (i) H, (ii) halogen, (iii)—CN, (iv) —CON(R⁸)₂, (v) —NR¹³C(O)R¹³, (vi) —SO₂N(R¹³)₂, (vii) C₁-C₃alkyl, (vii) C₁-C₃ alkoxy, (ix) —N(R¹³)₂, (x) C₃-C₆ cycloalkyl, (xi)C₆-C₁₀ aryl, (xii) 5-10 membered heteroaryl having 1, 2, or 3heteroatoms independently selected from N, O, and S, and (xiii) 4-6membered heterocyclyl having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S; wherein the C₁-C₃ alkyl, C₁-C₃ alkoxy, C₃-C₆cycloalkyl, C₆-C₁₀ aryl, 5-10 membered heteroaryl, or 4-6 memberedheterocyclyl is unsubstituted or substituted with 1, 2, or 3 R¹¹ groups;

or wherein R⁵ and R⁶, or R⁶ and R⁷ together with atoms to which they areattached form (i) a phenyl or (ii) a 5-6 membered heteroaryl having 1 or2 heteroatoms independently selected from N, O, and S, wherein thephenyl or the 5-6 membered heteroaryl is unsubstituted or substitutedwith 1, 2, or 3 R¹¹ groups;

each R⁸ is independently H or C₁-C₃ alkyl, wherein the C₁-C₃ alkyl isunsubstituted or substituted with 1, 2, or 3 R¹² groups; or wherein twoR⁸ groups together with the nitrogen they are attached to form a 4-6membered heterocyclic ring having 1 or 2 heteroatoms selected from thegroup consisting of N, O, or S, wherein the 4-6 membered heterocyclicring is unsubstituted or substituted with 1, 2, or 3 R¹² groups;

each R¹² is independently —OR¹³, C₁-C₃ alkyl, or —N(R¹³)₂; wherein theC₁-C₃ alkyl is unsubstituted or substituted with 1, 2, or 3 groupsindependently selected from —OR¹³ and —N(R¹³)₂;

each R¹¹ is independently selected from the group consisting of (i)—OR¹³, (ii) halogen, (iii) CN, (iv) —N(R⁸)₂, (v) —CON(R⁸)₂, (vi)—N(R¹³)COR¹³, (vii) —S(O)₂R¹³, (viii) C₁-C₃ alkyl, (ix) C₃-C₆cycloalkyl, (x) 4-6 membered heterocyclyl having 1, 2, or 3 heteroatomsindependently selected from N, O, and S, (xi) C₆-C₁₀ aryl, and (xii)5-10 membered heteroaryl having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S; and

each R¹³ is independently H or C₁-C₃ alkyl, wherein the C₁-C₃ alkyl isunsubstituted or substituted with 1, 2, or 3 R²² groups; and

each R²² is independently selected from the group consisting of halogen,—OH, C₁-C₃ alkyl, C₁-C₃ alkoxy, —NH₂, —NH(C₁-C₃ alkyl), —N(C₁-C₃ alkyl)₂wherein each C₁-C₃ alkyl is same or different, C₃-C₆ cycloalkyl, 4-6membered heterocyclyl with 1, 2, or 3 heteroatoms selected from N, O,and S, C₆-C₁₀ aryl, and 5-10 membered heteroaryl having 1, 2, or 3heteroatoms independently selected from N, O, and S.

In some embodiments of the compounds of Formula I and I-Z,

and the compound of Formula I or I-Z is of Formula II-Z:

wherein the variables W, X, Y, Z, J, A, R², R³, L¹, R²⁰, R²¹, m, n, andp are as defined above for Formula I.

In some embodiments of the compounds of Formula I, I-Z, I-E, and II-Z, Wis NH or S, X is CR⁵, Y is CR⁶, and Z is CR⁷. In some embodiments, W isNH or S, X is N, Y is CR⁶, and Z is CR⁷. In some embodiments, W is NH orS, X is CR⁵, Y is N, and Z is CR⁷. In some embodiments, W is NH or S, Xis CR⁵, Y is CR⁶, and Z is N. In some embodiments, W is NH or S, X is N,Y is N, and Z is CR⁷. In some embodiments, W is NH or S, X is CR⁵, Y isN, and Z is N. In some embodiments, W is NH or S, X is N, Y is CR⁶, andZ is N.

In some embodiments of the compounds of Formula I, I-Z, I-E, and II-Z, Wis S, X is CR⁵, Y is CR⁶, and Z is CR⁷. In some embodiments, W is S, Xis N, Y is CR⁶, and Z is CR⁷. In some embodiments, W is S, X is CR⁵, Yis N, and Z is CR⁷. In some embodiments, W is S, X is CR⁵, Y is CR⁶, andZ is N. In some embodiments, W is S, X is N, Y is N, and Z is CR⁷. Insome embodiments, W is S, X is CR⁵, Y is N, and Z is N. In someembodiments, W is S, X is N, Y is CR⁶, and Z is N.

In some embodiments of the compounds of Formula I, I-Z, I-E, and II-Z, Wis NH, X is CR⁵, Y is CR⁶, and Z is CR⁷. In some embodiments, W is NH, Xis N, Y is CR⁶, and Z is CR⁷. In some embodiments, W is NH, X is CR⁵, Yis N, and Z is CR⁷. In some embodiments, W is NH, X is CR⁵, Y is CR⁶,and Z is N. In some embodiments, W is NH, X is N, Y is N, and Z is CR⁷.In some embodiments, W is NH, X is CR⁵, Y is N, and Z is N. In someembodiments, W is NH, X is N, Y is CR⁶, and Z is N.

In some embodiments of the compounds of Formula I, I-E, and I-Z,

In some embodiments of the compounds of Formula I, I-Z and I-E, R

In some embodiments of the compounds of Formula I, I-Z and I-E,

In some embodiments of the compounds of Formula I, I-Z and I-E,

In some embodiments, of the compounds of Formula I, I-Z and I-E

In some embodiments of the compounds of Formula I, I-Z and I-E, is

In some embodiments, W is NH. In some embodiments, W is S.

In some embodiments of the compounds of Formula I, I-Z and I-E,

In some embodiments of the compounds of Formula I, I-Z and I-E,

is selected from the group consisting of

In some embodiments

is selected from the group consisting

In some embodiments,

is selected from the group consisting of

In some embodiments,

is selected from the group consisting of

In some embodiments,

is selected from the group consisting of

In some embodiments,

In some embodiments,

In some embodiments, the compound of Formula I, I-Z, or II-Z is ofFormula IIa-Z:

wherein the variables X, Y, Z, J, A, R², R³, L¹, R²⁰, R²¹, m, n, and pare as defined above for Formula I.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z, andIIa-Z, each R⁵, R⁶, and/or R⁷ is independently (i) H, (ii) halogen,(iii) —CN, (iv) —CON(R⁸)₂, (v) —NR¹³C(O)R¹³, (vi) —SO₂N(R¹³)₂, (vii)C₁-C₃ alkyl, (viii) C₁-C₃ alkoxy, (ix) —N(R¹³)₂, (x) C₃-C₆ cycloalkyl,(xi) C₆-C₁₀ aryl, (xii) 5-10 membered heteroaryl having 1, 2, or 3heteroatoms independently selected from N, O, and S, and (xiii) 4-6membered heterocyclyl having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S; wherein the C₁-C₃ alkyl, C₁-C₃ alkoxy, C₃-C₆cycloalkyl, C₆-C₁₀ aryl, 5-10 membered heteroaryl, or 4-6 memberedheterocyclyl is unsubstituted or substituted with 1, 2, or 3 R¹¹ groups.

In some embodiments for the compound of Formula I, I-Z, I-E, II-Z, andIIa-Z, each R⁵, R⁶, and/or R⁷ is independently selected from the groupconsisting of (i) H, (ii) halogen, (iii) —CN, (iv) —CON(R⁸)₂, (v)—NR¹³C(O)R¹³, (vi) —SO₂N(R¹³)₂, (vii) C₁-C₃ alkyl, (viii) C₁-C₃ alkoxy,(ix) —N(R¹³)₂, (x) C₃-C₆ cycloalkyl, (xi) C₆-C₁₀ aryl, (xii) 5-10membered heteroaryl having 1, 2, or 3 heteroatoms independently selectedfrom N, O, and S, and (xiii) 4-6 membered heterocyclyl having 1, 2, or 3heteroatoms independently selected from N, O, and S; wherein the C₁-C₃alkyl, C₁-C₃ alkoxy, C₃-C₆ cycloalkyl, C₆-C₁₀ aryl, 5-10 memberedheteroaryl, or 4-6 membered heterocyclyl is unsubstituted or substitutedwith one R¹¹ group.

In some embodiments for the compound of Formula I, I-Z, I-E, II-Z, andIIa-Z, each R⁵, R⁶, and/or R⁷ is independently selected from the groupconsisting of (i) H, (ii) halogen, (iii) —CN, (iv) —CON(R⁸)₂, (v)—NR¹³C(O)R¹³, (vi) —SO₂N(R¹³)₂, (vii) C₁-C₃ alkyl, (viii) C₁-C₃ alkoxy,(ix) —N(R¹³)₂, (x) C₃-C₆ cycloalkyl, (xi) C₆-C₁₀ aryl, (xii) 5-10membered heteroaryl having 1, 2, or 3 heteroatoms independently selectedfrom N, O, and S, and (xiii) 4-6 membered heterocyclyl having 1, 2, or 3heteroatoms independently selected from N, O, and S; wherein the C₁-C₃alkyl, C₁-C₃ alkoxy, C₃-C₆ cycloalkyl, C₆-C₁₀ aryl, 5-10 memberedheteroaryl, or 4-6 membered heterocyclyl is unsubstituted.

In some embodiments for the compound of Formula I, I-Z, I-E, II-Z, andIIa-Z, each R⁵, R⁶, and/or R⁷ is independently selected from the groupconsisting of (i) H, (ii) halogen, (iii) —CN, (iv) —CON(R⁸)₂, (v)—NR¹³C(O)R¹³, (vi) —SO₂N(R¹³)₂, (vii) C₁-C₃ alkyl, (viii) —N(R¹³)₂, (ix)C₃-C₆ cycloalkyl, and (x) 5-10 membered heteroaryl having 1, 2, or 3heteroatoms independently selected from N, O, and S; wherein the C₁-C₃alkyl, C₃-C₆ cycloalkyl or 5-10 membered heteroaryl is unsubstituted;each R⁸ is independently H or C₁-C₃ alkyl, wherein the C₁-C₃ alkyl isunsubstituted or substituted with 1, 2, or 3 R¹² groups; or wherein twoR groups together with the nitrogen they are attached to form a 4-6membered heterocyclic ring having 1 or 2 heteroatoms selected from thegroup consisting of N, O, or S, wherein the 4-6 membered heterocyclicring is unsubstituted or substituted with one R¹² group; each R¹² isindependently —OR¹³, C₁-C₃ alkyl, or —N(R¹³)₂, wherein the C₁-C₃ alkylis unsubstituted or substituted with —OR¹³ or —N(R¹³)₂; and each R¹³ isindependently H or C₁-C₃ alkyl.

In some embodiments for the compound of Formula I, I-Z, I-E, II-Z, andIIa-Z, each R⁵, R⁶, and/or R⁷ is independently selected from the groupconsisting of (i) H, (ii) halogen, (iii) —CN, (iv) —CON(R⁸)₂, (v) C₁-C₃alkyl, and (vi) C₃-C₆ cycloalkyl, wherein the C₁-C₃ alkyl or C₃-C₆cycloalkyl is unsubstituted; each R⁸ is independently H or C₁-C₃ alkyl,wherein the C₁-C₃ alkyl is unsubstituted or substituted with one R¹²group; R¹² is —OR¹³, C₁-C₃ alkyl, or —N(R¹³)₂; and each R¹³ isindependently H or C₁-C₃ alkyl.

In some embodiments for the compound of Formula I, I-Z, I-E, II-Z, andIIa-Z, each R⁵, R⁶, and/or R⁷ is independently selected from the groupconsisting of H, Br, —CN, —CONHR⁸, C₁-C₃ alkyl, and C₃-C₆ cycloalkyl,wherein the C₁-C₃ alkyl or C₃-C₆ cycloalkyl is unsubstituted; R⁸ isC₁-C₃ alkyl, wherein the C₁-C₃ alkyl is unsubstituted or substitutedwith one R¹² group; R¹² is —OR¹³ or —N(R¹³)₂; and each R¹³ isindependently C₁-C₃ alkyl. In some embodiments, each R⁵, R⁶, and/or R⁷is independently selected from the group consisting of H, Br, —CN,—CONHCH₂CH₂N(CH₂CH₃)₂, CH₃, and cyclopropyl.

In some embodiments of the compounds of Formula I, I-Z, I-E, and II-Z, Wis NH, X is CR⁵, Y is CR⁶, and Z is CR⁷; wherein each R⁵, R⁶, and R⁷ isindependently selected from the group consisting of (i) H, (ii) halogen,(iii) —CN, (iv) —CON(R⁸)₂, (v) C₁-C₃ alkyl, and (vi) C₃-C₆ cycloalkyl,wherein the C₁-C₃ alkyl or C₃-C₆ cycloalkyl is unsubstituted; each R⁸ isindependently H or C₁-C₃ alkyl, wherein the C₁-C₃ alkyl is unsubstitutedor substituted with one R¹² group; R¹² is —OR¹³, C₁-C₃ alkyl, or—N(R¹³)₂; and each R¹³ is independently H or C₁-C₃ alkyl. In someembodiments, W is NH, X is CR⁵, Y is CR⁶, and Z is CR⁷, wherein each R,R⁶, and R⁷ is independently selected from the group consisting of H, Br,—CN, —CONHR⁸, C₁-C₃ alkyl and C₃-C₆ cycloalkyl, wherein the C₁-C₃ alkylor C₃-C₆ cycloalkyl is unsubstituted; R⁸ is C₁-C₃ alkyl, wherein theC₁-C₃ alkyl is unsubstituted or substituted with one R¹² group; R¹² is—OR¹³ or —N(R¹³)₂; and each R¹³ is independently C₁-C₃ alkyl. In someembodiments, W is NH, X is CR⁵, Y is CR⁶, and Z is CR⁷; wherein each R⁵,R⁶, and R⁷ is independently selected from the group consisting of H, Br,—CN, —CONHCH₂CH₂N(CH₂CH₃)₂, CH₃, and cyclopropyl.

In some embodiments of the compounds of Formula I, I-Z, I-E, and II-Z, Wis NH, X is N, Y is CR⁶, and Z is CR⁷; wherein each R⁶ and R⁷ isindependently selected from the group consisting of (i) H, (ii) halogen,(iii) —CN, (iv) —CON(R⁸)₂, (v) C₁-C₃ alkyl, and (vi) C₃-C₆ cycloalkyl;wherein the C₁-C₃ alkyl or C₃-C₆ cycloalkyl is unsubstituted; each R isindependently H or C₁-C₃ alkyl, wherein the C₁-C₃ alkyl is unsubstitutedor substituted with one R¹² group; R¹² is —OR¹³, C₁-C₃ alkyl, or—N(R¹³)₂; and each R¹³ is independently H or C₁-C₃ alkyl. In someembodiments, W is NH, X is N, Y is CR⁶, and Z is CR⁷; wherein each R⁶and R⁷ is independently selected from the group consisting of (i) H,(ii) Br, (iii) —CN, (iv) —CONHR⁸, (v) C₁-C₃ alkyl and (vi) C₃-C₆cycloalkyl, wherein the C₁-C₃ alkyl or C₃-C₆ cycloalkyl isunsubstituted; R⁸ is C₁-C₃ alkyl, wherein the C₁-C₃ alkyl isunsubstituted or substituted with one R¹² group; R¹² is —OR¹³ or—N(R¹³)₂; and each R¹³ is independently C₁-C₃ alkyl. In someembodiments, W is NH, X is N, Y is CR⁶, and Z is CR⁷; wherein each R⁶and R⁷ is independently selected from the group consisting of H, Br,—CN, —CONHCH₂CH₂N(CH₂CH₃)₂, CH₃, and cyclopropyl.

In some embodiments of the compounds of Formula I, I-Z, I-E, and II-Z, Wis NH, X is CR⁵, Y is N, and Z is CR⁷; wherein each R⁵ and R⁷ isindependently selected from the group consisting of (i) H, (ii) halogen,(iii) —CN, (iv) —CON(R⁸)₂, (v) C₁-C₃ alkyl, and (vi) C₃-C₆ cycloalkyl;wherein the C₁-C₃ alkyl or C₃-C₆ cycloalkyl is unsubstituted; each R⁸ isindependently H or C₁-C₃ alkyl, wherein the C₁-C₃ alkyl is unsubstitutedor substituted with one R¹² group; R¹² is —OR¹³, C₁-C₃ alkyl, or—N(R¹³)₂; and each R¹³ is independently H or C₁-C₃ alkyl. In someembodiments, W is NH, X is CR⁵, Y is N, and Z is CR⁷; wherein each R⁵and R⁷ is independently (i) H, (ii) Br, (iii) —CN, (iv) —CONHR⁸, (v)C₁-C₃ alkyl or (vi) C₃-C₆ cycloalkyl, wherein the C₁-C₃ alkyl or C₃-C₆cycloalkyl is unsubstituted; R⁸ is C₁-C₃ alkyl, wherein the C₁-C₃ alkylis unsubstituted or substituted with one R¹² group; R¹² is —OR¹³ or—N(R¹³)₂; and each R¹³ is independently C₁-C₃ alkyl. In someembodiments, W is NH, X is CR⁵, Y is N, and Z is CR⁷; wherein each R⁵and R⁷ is independently selected from the group consisting of H, Br,—CN, —CONHCH₂CH₂N(CH₂CH₃)₂, CH₃, and cyclopropyl.

In some embodiments of the compounds of Formula I, I-Z, I-E, and II-Z, Wis NH, X is CR⁵, Y is CR⁶, and Z is N; wherein each R⁵ and R⁶ isindependently selected from the group consisting of (i) H, (ii) halogen,(iii) —CN, (iv) —CON(R⁸)₂, (v) C₁-C₃ alkyl, and (vi) C₃-C₆ cycloalkyl;wherein the C₁-C₃ alkyl or C₃-C₆ cycloalkyl is unsubstituted; each R⁸ isindependently H or C₁-C₃ alkyl, wherein the C₁-C₃ alkyl is unsubstitutedor substituted with one R¹² group; R¹² is —OR¹³, C₁-C₃ alkyl, or—N(R¹³)₂; and each R¹³ is independently H or C₁-C₃ alkyl. In someembodiments, W is NH, X is CR⁵, Y is CR⁶, and Z is N; wherein each R⁵and R⁶ is independently selected from the group consisting of (i) H,(ii) Br, (iii) —CN, (iv) —CONHR⁸, (v) C₁-C₃ alkyl or (vi) C₃-C₆cycloalkyl, wherein the C₁-C₃ alkyl or C₃-C₆ cycloalkyl isunsubstituted; R⁸ is C₁-C₃ alkyl, wherein the C₁-C₃ alkyl isunsubstituted or substituted with one R¹² group; R¹² is —OR¹³ or—N(R¹³)₂; and each R¹³ is independently C₁-C₃ alkyl. In someembodiments, W is NH, X is CR⁵, Y is CR⁶, and Z is N; wherein each R⁵and R⁶ is independently selected from the group consisting of H, Br,—CN, —CONHCH₂CH₂N(CH₂CH₃)₂, CH₃, and cyclopropyl.

In some embodiments of the compounds of Formula I, I-Z, I-E, and II-Z, Wis NH, X is N, Y is N, and Z is CR⁷; wherein R⁷ is selected from thegroup consisting of (i) H, (ii) halogen, (iii) —CN, (vi) —CON(R⁸)₂, (v)C₁-C₃ alkyl, and (vi) C₃-C₆ cycloalkyl; wherein the C₁-C₃ alkyl or C₃-C₆cycloalkyl is unsubstituted; each R⁸ is independently H or C₁-C₃ alkyl,wherein the C₁-C₃ alkyl is unsubstituted or substituted with one R¹²group; R¹² is —OR¹³, C₁-C₃ alkyl, or —N(R¹³)₂; and each R¹³ isindependently H or C₁-C₃ alkyl. In some embodiments, W is NH, X is N, Yis N, and Z is CR⁷; wherein R⁷ is selected from the group consisting of(i) H, (ii) Br, (iii) —CN, (iv) —CONHR⁸, (v) C₁-C₃ alkyl or (vi) C₃-C₆cycloalkyl, wherein the C₁-C₃ alkyl or C₃-C₆ cycloalkyl isunsubstituted; R⁸ is C₁-C₃ alkyl, wherein the C₁-C₃ alkyl isunsubstituted or substituted with one R¹² group; R¹² is —OR¹³ or—N(R¹³)₂; and each R¹³ is independently C₁-C₃ alkyl. In someembodiments, W is NH, X is N, Y is N, and Z is CR⁷; wherein R⁷ isselected from the group consisting of H, Br, —CN, —CONHCH₂CH₂N(CH₂CH₃)₂,CH₃, and cyclopropyl.

In some embodiments of the compounds of Formula I, I-Z, I-E, and II-Z, Wis NH, X is N, Y is CR⁶, and Z is N; wherein R⁶ is selected from thegroup consisting of (i) H, (ii) halogen, (iii) —CN, (iv) —CON(R⁸)₂, (v)C₁-C₃ alkyl, and (vi) C₃-C₆ cycloalkyl; wherein the C₁-C₃ alkyl or C₃-C₆cycloalkyl is unsubstituted; each R⁸ is independently H or C₁-C₃ alkyl,wherein the C₁-C₃ alkyl is unsubstituted or substituted with one R¹²group; R¹² is —OR¹³, C₁-C₃ alkyl, or —N(R¹³)₂; and each R¹³ isindependently H or C₁-C₃ alkyl. In some embodiments, W is NH, X is N, Yis CR⁶, and Z is N; wherein R⁶ is selected from the group consisting of(i) H, (ii) Br, (iii) —CN, (iv) —CONHR⁸, (v) C₁-C₃ alkyl or (vi) C₃-C₆cycloalkyl, wherein the C₁-C₃ alkyl or C₃-C₆ cycloalkyl isunsubstituted; R⁸ is C₁-C₃ alkyl, wherein the C₁-C₃ alkyl isunsubstituted or substituted with one R¹² group; R¹² is —OR¹³ or—N(R¹³)₂; and each R¹³ is independently C₁-C₃ alkyl. In someembodiments, W is NH, X is N, Y is CR⁶, and Z is N; wherein R⁶ isselected from the group consisting of H, Br, —CN, —CONHCH₂CH₂N(CH₂CH₃)₂,CH₃, and cyclopropyl.

In some embodiments of the compounds of Formula I, I-Z, I-E, and II-Z, Wis NH, X is CR⁵, Y is N, and Z is N; wherein R⁵ is selected from thegroup consisting of (i) H, (ii) halogen, (iii) —CN, (iv) —CON(R⁸)₂, (v)C₁-C₃ alkyl, and (vi) C₃-C₆ cycloalkyl; wherein the C₁-C₃ alkyl or C₃-C₆cycloalkyl is unsubstituted; each R⁸ is independently H or C₁-C₃ alkyl,wherein the C₁-C₃ alkyl is unsubstituted or substituted with one R¹²group; R¹² is —OR¹³, C₁-C₃ alkyl, or —N(R¹³)₂; and each R¹³ isindependently H or C₁-C₃ alkyl. In some embodiments, W is NH, X is CR⁵,Y is N, and Z is N; wherein R⁵ is selected from the group consisting ofH, Br, —CN, —CONHR⁸, C₁-C₃ alkyl or C₃-C₆ cycloalkyl, wherein the C₁-C₃alkyl or C₃-C₆ cycloalkyl is unsubstituted; R⁸ is C₁-C₃ alkyl, whereinthe C₁-C₃ alkyl is unsubstituted or substituted with one R¹² group; R¹²is —OR¹³ or —N(R¹³)₂; and each R¹³ is independently C₁-C₃ alkyl. In someembodiments, W is NH, X is CR⁵, Y is N, and Z is N; wherein R⁵ isselected from the group consisting of H, Br, —CN, —CONHCH₂CH₂N(CH₂CH₃)₂,CH₃, and cyclopropyl.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z, andIIa-Z, each R⁵, R⁶, and R⁷ is independently H, halogen, —CN, —CON(R⁸)₂,—NR¹³C(O)R¹³, —SO₂N(R¹³)₂, C₁-C₃ alkyl, 5-6 membered heteroaryl having 1or 2 heteroatoms independently selected from N, O and S, or C₃-C₆cycloalkyl; wherein the C₁-C₃ alkyl or the C₃-C₆ cycloalkyl isunsubstituted or substituted with 1, 2, or 3 R¹¹ groups. In someembodiments, each R⁵, R⁶, and R⁷ is independently H, halogen, —CN,—CON(R⁸)₂, —SO₂N(R¹³)₂, C₁-C₃ alkyl, or C₃-C₆ cycloalkyl; wherein theC₁-C₃ alkyl or the C₃-C₆ cycloalkyl is unsubstituted or substituted with1, 2, or 3 R¹¹ groups. In some embodiments, each R⁵, R⁶ and R⁷ isindependently H, Br, CN, —CON(R⁸)₂, —SO₂N(R¹³)₂, C₁-C₃ alkyl, or C₃-C₆cycloalkyl; wherein the C₁-C₃ alkyl or the C₃-C₆ cycloalkyl isunsubstituted. In some embodiments, each R⁵, R⁶ and R⁷ is independentlyH, CN, Br, —CONHCH₂CH₂N(CH₂CH₃)₂, —CONH(CH₃), —SO₂NHCH₃, —CH₃, —CH₂CH₃,or cyclopropyl.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z, andIIa-Z, R⁵ is H, C₁-C₃ alkyl, or C₃-C₆ cycloalkyl. In some embodiments,R⁵ is H, —CH₃, —CH₂CH₃, or cyclopropyl.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z, andIIa-Z, R⁶ is H, halogen, —CN, C₁-C₃ alkyl, or CON(R⁸)₂. In someembodiments, R⁶ is H, Br, CN, C₁-C₃ alkyl, or —CONHCH₂CH₂N(CH₂CH₃)₂.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z, andIIa-Z, R⁷ is H or CH₃.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z, andIIa-Z, each R⁵, R⁶, and R⁷ is H.

In some embodiments, of the compounds of Formula I, I-Z, I-E, II-Z, andIIa-Z, X is CR⁵ and Y is CR⁶, wherein R⁵ and R⁶ together with atoms towhich they are attached form (i) a phenyl or (ii) a 5 or 6 memberedheteroaryl having 1 or 2 heteroatoms independently selected from N, O,and S; wherein the phenyl or the 5 or 6 membered heteroaryl isunsubstituted or substituted with 1, 2, or 3 R¹¹ groups. In someembodiments, the phenyl or the 5 or 6 membered heteroaryl isunsubstituted or substituted with one R¹¹ group. In some embodiments,the phenyl or the 5 or 6 membered heteroaryl is unsubstituted.

In some embodiments, of the compounds of Formula I, I-Z, I-E, II-Z, andIIa-Z, X is CR⁵ and Y is CR⁶, wherein R⁵ and R⁶ together with atoms towhich they are attached form (i) a phenyl or (ii) a 5 or 6 memberedheteroaryl having 1 or 2 heteroatoms independently selected from N andS; wherein the phenyl or the 5 or 6 membered heteroaryl is unsubstitutedor substituted with 1, 2, or 3 R¹¹ groups. In some embodiments, thephenyl or the 5 or 6 membered heteroaryl is unsubstituted or substitutedwith one R¹¹ group. In some embodiments, the phenyl or the 5 or 6membered heteroaryl is unsubstituted.

In some embodiments, of the compounds of Formula I, I-Z, I-E, II-Z, andIIa-Z, X is CR⁵ and Y is CR⁶, wherein R⁵ and R⁶ together with atoms towhich they are attached form (i) phenyl, (ii) pyridyl or (iii)thiozolyl; wherein the (i) phenyl, (ii) pyridyl or (iii) thiozolyl isunsubstituted or substituted with 1, 2, or 3 R¹¹ groups. In someembodiments, the phenyl, pyridyl or thiozolyl is unsubstituted orsubstituted with one R¹¹ group. In some embodiments, the phenyl, pyridylor thiozolyl is unsubstituted.

In some embodiments, the compound of Formula I, I-Z, II-Z, and IIa-Z isa compound of Formula IIb-Z:

wherein the variables Z, J, A, R², R³, L¹, R²⁰, R²¹, m, n, and p are asdefined above for Formula I;

L is N or CR¹⁵;

M is N or CR¹⁶;

Q is N or CR¹⁷; and

R is N or CR¹⁸;

wherein each R¹⁵, R¹⁶, R¹⁷, and R¹⁸ is independently selected from thegroup consisting of H, halogen, CN, —N(R⁸)₂, —CON(R⁸)₂, —N(R¹³)COR¹³,—S(O)₂R¹³, C₁-C₃ alkyl, C₁-C₃ alkoxy, C₆-C₁₀ aryl, 5-10 memberedheteroaryl having 1, 2, or 3 heteroatoms independently selected from N,O, and S, and 4-6 membered heterocyclyl having 1, 2, or 3 heteroatomsindependently selected from N, O, and S.

In some embodiments of the compounds of Formula I and I-Z,

is a group of formula

and the compound is of Formula III-Z:

wherein the variables Y, Z, J, A, R², R³, L¹, R²⁰, R²¹, m, n, and p areas defined above for Formula I.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, and III-Z, Y is CR⁶ and Z is CR⁷, wherein R⁶ and R⁷ together withatoms to which they are attached form (i) a phenyl or (ii) a 5 or 6membered heteroaryl having 1 or 2 heteroatoms independently selectedfrom N, O, and S; wherein the phenyl or the 5 or 6 membered heteroarylis unsubstituted or substituted with 1, 2, or 3 R¹¹ groups. In someembodiments, the phenyl or the 5 or 6 membered heteroaryl isunsubstituted or substituted with one R¹¹ group. In some embodiments,the phenyl or the 5 or 6 membered heteroaryl is unsubstituted.

In some embodiments, of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, and III-Z, Y is CR⁶ and Z is CR⁷, wherein R⁶ and R⁷ together withatoms to which they are attached form (i) a phenyl or (ii) a 5 or 6membered heteroaryl having 1 or 2 heteroatoms independently selectedfrom N and S; wherein the phenyl or the 5 or 6 membered heteroaryl isunsubstituted or substituted with 1, 2, or 3 R¹¹ groups. In someembodiments, the phenyl or the 5 or 6 membered heteroaryl isunsubstituted or substituted with one R¹¹ group. In some embodiments,the phenyl or the 5 or 6 membered heteroaryl is unsubstituted.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, and III-Z, Y is CR⁶ and Z is CR⁷, wherein R⁶ and R⁷ together withatoms to which they are attached form a (i) phenyl, (ii) pyridyl or(iii) thiozolyl; wherein the phenyl, pyridyl or thiozolyl isunsubstituted or substituted with 1, 2, or 3 R¹¹ groups. In someembodiments, the phenyl, pyridyl or thiozolyl is unsubstituted orsubstituted with one R¹¹ group. In some embodiments, the phenyl, pyridylor thiozolyl is unsubstituted.

In some embodiments, of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, and III-Z, R¹¹ is selected from the group consisting of (i) CN,(ii) —N(R⁸)₂, (iii) —N(R¹³)COR¹³, and (iv) 4-6 membered heterocyclylhaving 1, 2, or 3, heteroatoms independently selected from N, O, and S;wherein each R¹³ is independently H or C₁-C₃ alkyl. In some embodiments,R¹¹ is selected from the group consisting of (i) —CN, (ii) —NH₂, (iii)—NHCOR¹³, and (iv) 6 membered heterocyclyl having 1 or 2 heteroatomsindependently selected from N and O; wherein R¹³ is C₁-C₃ alkyl. In someembodiments, R¹¹ is selected from the group consisting of CN, —NH₂,—NHCOCH₃, and morpholinyl. In some embodiments, of the compoundsprovided herein R¹¹ is absent.

In some embodiments the compound of Formula I, I-Z or III-Z, is acompound of Formula IIIa-Z:

wherein the variables J, A, R², R³, L¹, R²⁰, R²¹, m, n, and p are asdefined above for Formula I; and L, M, Q, and R are as defined above forFormula IIb-Z.

In some embodiments of the compounds of Formula IIb-Z and IIIa-Z, L isCR, M is CR¹⁶, Q is CR¹⁷, and R is CR¹⁸; wherein each R, R¹⁶, R¹⁷, andR¹⁸ is independently selected from the group consisting of (i) H, (ii)halogen, (iii) CN, (iv) —N(R⁸)₂, (v) —CON(R⁸)₂, (vi) —N(R¹³)COR¹³, (vii)—S(O)₂R¹³, (viii) C₁-C₃ alkyl, (ix) C₁-C₃ alkoxy, (x) C₆-C₁₀ aryl, (xi)5-10 membered heteroaryl having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S, and (xii) 4-6 membered heterocyclyl having 1,2, or 3 heteroatoms independently selected from N, O, and S. In someembodiments, L is CR¹⁵, M is CR¹⁶, Q is CR¹⁷, and R is CR¹⁸; whereineach R¹⁵, R¹⁶, R¹⁷, and R¹⁸ is independently (i) H, (ii) CN, (iii) NH₂,or (vi) NHCOCH₃. In some embodiments, L is CR¹⁵, M is CR¹⁶, Q is CR¹⁷,and R is CR¹⁸; wherein each R¹⁵, R¹⁶, R¹⁷, and R¹⁸ is H.

In some embodiments of the compounds of Formula IIb-Z and IIIa-Z, L isN, M is CR¹⁶, Q is CR¹⁷, and R is CR¹⁸; wherein each R¹⁶, R¹⁷, and R¹⁸is independently selected from the group consisting of (i) H, (ii)halogen, (iii) CN, (iv) —N(R⁸)₂, (v) —CON(R⁸)₂, (vi) —N(R¹³)COR¹³, (vii)—S(O)₂R¹³, (viii) C₁-C₃ alkyl, (ix) C₁-C₃ alkoxy, (x) C₆-C₁₀ aryl, (xi)5-10 membered heteroaryl having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S, and (xii) 4-6 membered heterocyclyl having 1,2, or 3 heteroatoms independently selected from N, O, and S. In someembodiments, L is N, M is CR¹⁶, Q is CR¹⁷, and R is CR¹⁸; wherein eachR¹⁶, R¹⁷, and R¹⁸ is independently (i) H, (ii) CN, (iii) NH₂, or (iv)NHCOCH₃. In some embodiments, L is N, M is CR¹⁶, Q is CR¹⁷, and R isCR¹⁸; wherein each R¹⁶, R¹⁷, and R¹¹ is H.

In some embodiments of the compounds of Formula IIb-Z and IIIa-Z, L isCR¹⁵, M is N, Q is CR⁷, and R is CR¹⁸; wherein each R¹⁵, R¹⁷, and R¹⁸ isindependently selected from the group consisting of (i) H, (ii) halogen,(iii) CN, (iv) —N(R⁸)₂, (v) —CON(R⁸)₂, (vi) —N(R¹³)COR¹³, (vii)—S(O)₂R¹³, (viii) C₁-C₃ alkyl, (ix) C₁-C₃ alkoxy, (x) C₆-C₁₀ aryl, (xi)5-10 membered heteroaryl having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S, and (xii) 4-6 membered heterocyclyl having 1,2, or 3 heteroatoms independently selected from N, O, and S. In someembodiments, L is CR¹⁵, M is N, Q is CR¹⁷, and R is CR¹⁸; wherein eachR¹⁵, R¹⁷, and R¹⁸ is independently (i) H, (ii) CN, (iii) NH₂, or (iv)NHCOCH₃. In some embodiments, L is CR¹⁵, M is N, Q is CR¹⁷, and R isCR¹⁸; wherein each R¹⁵, R¹⁷, and R¹⁸ is H.

In some embodiments of the compounds of Formula IIb-Z and IIIa-Z, L isCR¹⁵, M is CR¹⁶, Q is N, and R is CR¹⁸; wherein each R, R¹⁶, and R¹⁸ isindependently selected from the group consisting of (i) H, (ii) halogen,(iii) CN, (iv) —N(R⁸)₂, (v) —CON(R⁸)₂, (vi) —N(R¹³)COR¹³, (vii)—S(O)₂R¹³, (viii) C₁-C₃ alkyl, (ix) C₁-C₃ alkoxy, (x) C₆-C₁₀ aryl, (xi)5-10 membered heteroaryl having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S, and (xii) 4-6 membered heterocyclyl having 1,2, or 3 heteroatoms independently selected from N, O, and S. In someembodiments, L is CR¹⁵, M is CR¹⁶, Q is N, and R is CR; wherein eachR¹⁵, R¹⁶, and R¹⁸ is independently H, CN, NH₂, or NHCOCH₃. In someembodiments, L is CR¹⁵, M is CR¹⁶, Q is N, and R is CR¹⁸; wherein eachR¹⁵, R¹⁶, and R¹⁸ is H.

In some embodiments of the compounds of Formula IIb-Z and IIIa-Z, L isCR¹⁵, M is CR¹⁶, Q is CR¹⁷, and R is N; wherein each R¹⁵, R¹⁶, and R¹⁷is independently selected from the group consisting of (i) H, (ii)halogen, (iii) CN, (iv) —N(R⁸)₂, (v) —CON(R⁸)₂, (vi) —N(R¹³)COR¹³, (vii)—S(O)₂R¹³, (viii) C₁-C₃ alkyl, (ix) C₁-C₃ alkoxy, (x) C₆-C₁₀ aryl, (xi)5-10 membered heteroaryl having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S, and (xii) 4-6 membered heterocyclyl having 1,2, or 3 heteroatoms independently selected from N, O, and S. In someembodiments, L is CR¹⁵, M is CR¹⁶, Q is CR¹⁷, and R is N; wherein eachR¹⁵, R¹⁶, and R¹⁷ is independently H, CN, NH₂, or NHCOCH₃. In someembodiments, L is CR¹⁵, M is CR¹⁶, Q is CR¹⁷, and R is N; wherein eachR⁵, R¹⁶, and R¹⁷ is H.

In some embodiments of the compounds of Formula IIb-Z and IIIa-Z, eachR, R¹⁶, R¹⁷, and R¹⁸ is independently selected from the group consistingof H, CN, —N(R⁸)₂, and —N(R¹³)COR¹³. In some embodiments, R⁵, R¹⁶, R¹⁷,and R¹⁸ are each H.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, each R is independently H or C₁-C₃alkyl, wherein the C₁-C₃ alkyl is unsubstituted or substituted with 1,2, or 3 R¹² groups. In some embodiments, R⁸ is H or C₁-C₃ alkyl, whereinthe C₁-C₃ alkyl is unsubstituted substituted with one R¹² group. In someembodiments, R⁸ is H or C₁-C₃ alkyl, wherein the C₁-C₃ alkyl isunsubstituted. In some embodiments, R⁸ is H. In some embodiments, R⁸ isC₁-C₃ alkyl. In some embodiments, R⁸ is H or C₁-C₃ alkyl substitutedwith —N(R¹³)₂, wherein R¹³ is H or C₁-C₃ alkyl. In some embodiments, R⁸is H or C₁-C₃ alkyl substituted with —N(CH₂CH₃)₂.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, two R⁸ groups together with thenitrogen they are attached to form a 4-6 membered heterocyclic ringhaving 1 or 2 heteroatoms selected from the group consisting of N, O, orS, wherein the 4-6 membered heterocyclic ring is unsubstituted orsubstituted with 1, 2, or 3 R¹² groups.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, two R⁸ groups together with thenitrogen they are attached to form a 4-6 membered heterocyclic ringhaving 1 or 2 heteroatoms selected from the group consisting of N, O, orS, wherein the 4-6 membered heterocyclic ring is unsubstituted orsubstituted with one R¹² group.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, two R⁸ groups together with thenitrogen they are attached to form a 4-6 membered heterocyclic ringhaving 1 or 2 heteroatoms selected from the group consisting of N, O, orS, wherein the 4-6 membered heterocyclic ring is unsubstituted.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, two R⁸ groups together with thenitrogen they are attached to form a 6 membered heterocyclic ring having2 heteroatoms selected from the group consisting of N, O, or S, whereinthe 6 membered heterocyclic ring is unsubstituted or substituted withone R¹² group.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, two R⁸ groups together with thenitrogen they are attached to form a 6 membered heterocyclic ring having2 heteroatoms selected from N and S, wherein the 6 membered heterocyclicring is unsubstituted or substituted with one R¹² group.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, each R¹² is independently —OR³, C₁-C₃alkyl, or —N(R¹³)₂; wherein each R¹³ is independently H or C₁-C₃ alkyl.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, A is N or CR¹, and each R, R², and R³is independently selected from the group consisting of (i) H, (ii)halogen, (iii) —CN, (iv) —N(R¹³)₂, (v) C₁-C₃ alkyl, (vi) C₂-C₃ alkynyl,(vii) C₁-C₃ alkoxy, or -(viii) SO₂R¹³, wherein the C₂-C₃ alkynyl isunsubstituted or substituted with 1, 2, or 3 R⁹ groups; each R⁹ isindependently —OR¹³, C₁-C₃ alkyl, or C₃-C₆ cycloalkyl; and each R¹³ isindependently H or C₁-C₃ alkyl.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, A is N or CR¹, and each R, R², and R³is independently selected from (i) H, (ii) halogen, (iii) —CN, (iv)C₁-C₃ alkyl, (v) C₂-C₃ alkynyl, (vi) C₁-C₃ alkoxy, or (vii) —SO₂R¹³,wherein the C₂-C₃ alkynyl is unsubstituted or substituted with one, twoor three R⁹ groups; each R⁹ is independently —OR¹³, C₁-C₃ alkyl, orC₃-C₆ cycloalkyl; and each R¹³ is independently H or C₁-C₃ alkyl.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, A is N or CR¹, and each R, R², and R³is independently selected from the group consisting of H, F, Cl, —CN,—CH₃, —OCH₃, C₂-C₃ alkynyl, or —SO₂R¹³, wherein the C₂-C₃ alkynyl isunsubstituted or substituted with one, two or three R⁹ groups; each R⁹is independently —OH, —CH₃, or cyclopropyl.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, A is N or CR¹; and each R, R², and R³is independently selected from the group consisting of H, halogen, andC₁-C₃ alkyl. In some embodiments, A is N or CR¹, and each R¹, R², and R³is independently selected from H, F, C₁, and C₁-C₃ alkyl. In someembodiments, A is N or CR¹, and each R, R², and R³ is independentlyselected from H, F, Cl and CH₃.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, A is N or CR¹; wherein R is H, halogen,—CN, —N(R¹³)₂, C₁-C₃ alkyl, C₂-C₃ alkynyl, C₁-C₃ alkoxy, or —SO₂R¹³,wherein the C₂-C₃ alkynyl is unsubstituted or substituted with 1, 2, or3 R⁹ groups; each R⁹ is independently —OR¹³, C₁-C₃ alkyl, or C₃-C₆cycloalkyl; and each R¹³ is independently H or C₁-C₃ alkyl. In someembodiments, A is N or CR¹; wherein R¹ is H, halogen or C₁-C₃ alkyl. Insome embodiments, A is N or CR¹; wherein R¹ is H, F, Cl or C₁-C₃ alkyl.In some embodiments, A is N or CR¹; wherein R¹ is H, F, Cl or CH₃.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, A is CR¹; wherein R¹ is H, halogen,—CN, —N(R¹³)₂, C₁-C₃ alkyl, C₂-C₃ alkynyl, C₁-C₃ alkoxy, or —SO₂R¹³,wherein the C₂-C₃ alkynyl is unsubstituted or substituted with 1, 2, or3 R⁹ groups; each R⁹ is independently —OR¹³, C₁-C₃ alkyl, or C₃-C₆cycloalkyl; and each R¹³ is independently H or C₁-C₃ alkyl. In someembodiments, A is CR¹; wherein R¹ is H, halogen or C₁-C₃ alkyl. In someembodiments, A is CR¹; wherein R¹ is H, F, Cl or C₁-C₃ alkyl. In someembodiments, A is CR¹; wherein R¹ is H, F, Cl or CH₃.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, A is N.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, R² is (i) H, (ii) halogen, (iii) —CN,(iv) —N(R¹³)₂, (v) C₁-C₃ alkyl, (vi) C₂-C₃ alkynyl, (vii) C₁-C₃ alkoxy,or (viii) —SO₂R¹³, wherein the C₂-C₃ alkynyl is unsubstituted orsubstituted with 1, 2, or 3 R⁹ groups; each R⁹ is independently —OR¹³,C₁-C₃ alkyl, or C₃-C₆ cycloalkyl; and each R¹³ is independently H orC₁-C₃ alkyl. In some embodiments, R² is (i) H, (ii) halogen, (iii) —CN,(iv) C₁-C₃ alkyl, (v) C₂-C₃ alkynyl, (vi) C₁-C₃ alkoxy, or (vii)—SO₂R¹³, wherein the C₂-C₃ alkynyl is unsubstituted or substituted with1, 2, or 3 R⁹ groups; each R⁹ is independently —OR¹³, C₁-C₃ alkyl, orC₃-C₆ cycloalkyl; and each R¹³ is independently H or C₁-C₃ alkyl. Insome embodiments, R² is H, F, Cl, —CN, —CH₃, —OCH₃, C₂-C₃ alkynyl, or—SO₂R¹³ wherein the C₂-C₃ alkynyl is unsubstituted or substituted withone, two or three R⁹ groups; each R⁹ is independently —OH, —CH₃, orcyclopropyl. In some embodiments, R² is H, F, Cl or C₁-C₃ alkyl. In someembodiments, R² is H, F, Cl or CH₃.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, R³ is (i) H, (ii) halogen, (iii) —CN,(iv) —N(R¹³)₂, (v) C₁-C₃ alkyl, (vi) C₂-C₃ alkynyl, (vii) C₁-C₃ alkoxy,or (viii) —SO₂R¹³, wherein the C₂-C₃ alkynyl is unsubstituted orsubstituted with 1, 2, or 3 R⁹ groups; each R⁹ is independently —OR¹³,C₁-C₃ alkyl, or C₃-C₆ cycloalkyl; and each R¹³ is independently H orC₁-C₃ alkyl. In some embodiments, R³ is H or C₁-C₃ alkyl. In someembodiments, R³ is H or —CH₃. In some embodiments, R³ is H. In someembodiments, R³ is C₁-C₃ alkyl. In some embodiments, R³ is —CH₃.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, each R, R², and R³ is independently H,halogen, C₁-C₃ alkyl, or C₂-C₃ alkynyl, wherein the C₂-C₃ alkynyl isunsubstituted or substituted with 1, 2, or 3 R⁹ groups. In someembodiments, each R¹, R², and R³ is independently H, F, C₁, C₁-C₃ alkyl,or C₂-C₃ alkynyl, wherein the C₂-C₃ alkynyl is unsubstituted orsubstituted with 1, 2, or 3 groups independently selected from the groupconsisting of OH, CH₃, and cyclopropyl.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, both R¹ and R³ are H.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, R² is H, halogen, CN, —N(R¹³)₂, C₁-C₃alkoxy, C₁-C₃ alkyl, or C₂-C₃ alkynyl, wherein the C₂-C₃ alkynyl isunsubstituted or substituted with 1, 2, or 3 R⁹ groups. In someembodiments, R² is H, halogen, C₁-C₃ alkyl, or C₂-C₃ alkynyl, whereinthe C₂-C₃ alkynyl is unsubstituted or substituted with 1, 2, or 3 R⁹groups. In some embodiments, R² is H, Cl, F, —CH₃, —CN, —NH₂, —SO₂CH₃,—OCH₃,

In some embodiments, R² is H, Cl, F, or CH₃.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, R⁹ is —OH, CH₃, or cyclopropyl.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, R is H, halogen or C₁-C₃ alkyl. In someembodiments, R¹ is H, F, C₁, or CH₃.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, R¹ is F or C₁ and R² is H.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, R¹ is F or C₁; R² is H; and R³ is H orC₁-C₃ alkyl. In some embodiments, R¹ is F or C₁; R² is H; and R³ is CH3.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, R¹ is CH₃; R² is H; and R³ is H.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, R¹, R², and R³ is H.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, J is H, —CN, C₁-C₃ alkyl, or C₃-C₆cycloalkyl, wherein the C₁-C₃ alkyl or C₃-C₆ cycloalkyl is unsubstitutedor substituted with 1, 2, or 3 R¹⁰ groups; each R¹⁰ is independentlyselected from the group consisting of (i) —OR¹³, (ii) halogen, (iii) CN,(iv) —N(R⁸)₂, (v) —CON(R⁸)₂, (vi) —N(R¹³)COR¹³, (vii) —S(O)₂R¹³, (viii)C₁-C₃ alkyl, (ix) C₃-C₆ cycloalkyl, (x) 4-6 membered heterocyclyl having1, 2, or 3 heteroatoms independently selected from N, O, and S, (xi)C₆-C₁₀ aryl, and (xii) 5-10 membered heteroaryl having 1, 2, or 3heteroatoms independently selected from N, O, and S; and each R¹³ isindependently H or C₁-C₃ alkyl.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, J is H, —CN, C₁-C₃ alkyl, or C₃-C₆cycloalkyl, wherein the C₁-C₃ alkyl or C₃-C₆ cycloalkyl is unsubstitutedor substituted with one R¹⁰ group; R¹ is selected from the groupconsisting of (i) —OR¹³, (ii) halogen, (iii) CN, (iv) —N(R⁸)₂, (v)—CON(R⁸)₂, (vi) —N(R¹³)COR¹³, (vii) —S(O)₂R¹³, (viii) C₁-C₃ alkyl, (ix)C₃-C₆ cycloalkyl, (x) 4-6 membered heterocyclyl having 1, 2, or 3heteroatoms independently selected from N, O, and S, (xi) C₆-C₁₀ aryl,and (xii) 5-10 membered heteroaryl having 1, 2, or 3 heteroatomsindependently selected from N, O, and S; and each R¹³ is independently Hor C₁-C₃ alkyl.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, J is H or C₁-C₃ alkyl, wherein theC₁-C₃ alkyl is unsubstituted or substituted with one R¹⁰ group; R¹⁰ isselected from the group consisting of (i) —OR¹³, (ii) halogen, (iii) CN,(iv) —N(R⁸)₂, (v) —CON(R⁸)₂, (vi) —N(R¹³)COR¹³, (vii) —S(O)₂R¹³, (viii)C₁-C₃ alkyl, (ix) C₃-C₆ cycloalkyl, (x) 4-6 membered heterocyclyl having1, 2, or 3 heteroatoms independently selected from N, O, and S, (xi)C₆-C₁₀ aryl, and (xii) 5-10 membered heteroaryl having 1, 2, or 3heteroatoms independently selected from N, O, and S; and each R¹³ isindependently H or C₁-C₃ alkyl.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, J is H or C₁-C₃ alkyl, wherein theC₁-C₃ alkyl is unsubstituted or substituted with 1, 2, or 3 R^(1I)group; R¹ is selected from the group consisting of (i) —OR¹³, (ii)halogen, (iii) CN, (iv) —N(R⁸)₂, (v) C₁-C₃ alkyl, and (vi) C₃-C₆cycloalkyl; wherein each R¹³ is independently H or C₁-C₃ alkyl. In someembodiments, J is H or C₁-C₃ alkyl, wherein the C₁-C₃ alkyl isunsubstituted or substituted with 1, 2, or 3 R¹⁰ group; and R¹⁰ isselected from the group consisting of (i) —OH, (ii) halogen, (iii) CN,(iv) —NH₂, (v) C₁-C₃ alkyl, and (vi) C₃-C₆ cycloalkyl.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, J is H, —CN, unsubstituted C₁-C₃ alkyl,or unsubstituted C₃-C₆ cycloalkyl. In some embodiments, J is H,unsubstituted C₁-C₃ alkyl, or unsubstituted C₃-C₆ cycloalkyl. In someembodiments, J is H or unsubstituted C₁-C₃ alkyl. In some embodiments, Jis H, methyl or ethyl. In some embodiments, J is H. In some embodiments,J is C₁-C₃ alkyl. In some embodiments, J is methyl or ethyl.

In some embodiments of the compounds of Formula I, I-Z, and I-E,

is selected from the group consisting of

In some embodiments,

In some embodiments,

In some embodiments

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, L is N or CR¹⁹, wherein R¹⁹ is H,—OR¹³, halogen, CN, —N(R¹³)₂, or C₁-C₃ alkyl; and each R¹³ isindependently H or C₁-C₃ alkyl. In some embodiments, L¹ is N or CR¹⁹,wherein R¹⁹ is H or C₁-C₃ alkyl. In some embodiments, L¹ is N or CR¹⁹,wherein R¹⁹ is H or CH₃. In some embodiments, L¹ is N or CR¹⁹, whereinR¹⁹ is H.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, L is CR¹⁹, wherein R¹⁹ is H, —OR¹³,halogen, CN, —N(R¹³)₂, or C₁-C₃ alkyl; and wherein each R¹³ isindependently H or C₁-C₃ alkyl. In some embodiments, L¹ is CR¹⁹, whereinR¹⁹ is H or C₁-C₃ alkyl. In some embodiments, L¹ is CR¹⁹, wherein R¹⁹ isH or CH₃. In some embodiments, L¹ is CR¹⁹, wherein R¹⁹ is H.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, L¹ is N.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, n is 1. In some embodiments, n is 0. Insome embodiments, n is 2.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, n is 1 and L is CR¹⁹; wherein R¹⁹ is Hor C₁-C₃ alkyl, for example, R¹⁹ is H or CH₃, or R¹⁹ is H. In someembodiments, n is 0 and L¹ is CR¹⁹; wherein R¹⁹ is H or C₁-C₃ alkyl, forexample, R¹⁹ is H or CH₃, or R¹⁹ is H. In some embodiments, n is 2 and Lis CR¹⁹; wherein R¹⁹ is H or C₁-C₃ alkyl, for example, R¹⁹ is H or CH₃,or R¹⁹ is H.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, n is 1 and L is N. In some embodiments,n is 0 and L¹ is N. In some embodiments, n is 2 and L¹ is N.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, m is 0, 1, 2, or 3; each R²⁰ isindependently —OR¹³, halogen, CN, —N(R¹³)₂, or C₁-C₃ alkyl; and each R¹³is independently H or C₁-C₃ alkyl. In some embodiments, m is 0, 1, 2, or3; and each R²⁰ is independently C₁-C₃ alkyl. In some embodiments, m is0 or 1; and R²⁰ is C₁-C₃ alkyl. In some embodiments, m is 0. In someembodiments, m is 1; and R²⁰ is C₁-C₃ alkyl. In some embodiments, m is 0or 1 and R²⁰ is CH₃. In some embodiments, m is 1 and R²⁰ is CH₃.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, L¹ is CR¹⁹ or N; n is 1; m is 0; and pis 0. In some embodiments, L¹ is CR¹⁹ or N; n is 0; m is 0; and p is 0.In some embodiments, L¹ is CR¹⁹ or N; n is 2; m is 0; and p is 0. Insome embodiments, L¹N; n is 1; m is 0; and p is 0. In some embodiments,L¹ is N; n is 0; m is 0; and p is 0. In some embodiments, L is N; n is2; m is 0; and p is 0.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, L¹ is CR¹⁹; n is 1; m is 0; and p is 0;R¹⁹ is H, —OR¹³, halogen, CN, —N(R¹³)₂, or C₁-C₃ alkyl; and each R¹³ isindependently H or C₁-C₃ alkyl. In some embodiments, L¹ is CR¹⁹; n is 1;m is 0; and p is 0; wherein R¹⁹ is H, —OH, halogen, CN, —NH₂, or C₁-C₃alkyl. In some embodiments, L¹ is CR¹⁹; n is 1; m is 0; p is 0; and R¹⁹is H.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, L is CR¹⁹; n is 0; m is 0; and p is 0;wherein R¹⁹ is H, —OR¹³, halogen, CN, —N(R¹³)₂, or C₁-C₃ alkyl; and eachR¹³ is independently H or C₁-C₃ alkyl. In some embodiments, L¹ is CR¹⁹;n is 0; m is 0; and p is 0; wherein R¹⁹ is H, —OH, halogen, CN, —NH₂, orC₁-C₃ alkyl. In some embodiments of the compounds of Formula I, II, IIa,IIb, and IIIa, L¹ is CR¹⁹; n is 0; m is 0; p is 0; and R¹⁹ is H.

In some embodiments of the compounds of I, I-Z, I-E, II-Z, IIa-Z, IIb-Z,III-Z, and IIIa-Z, L¹ is CR¹⁹; n is 2; m is 0; and p is 0; wherein R¹⁹is H, —OR¹³, halogen, CN, —N(R¹³)₂, or C₁-C₃ alkyl; and each R¹³ isindependently H or C₁-C₃ alkyl. In some embodiments, L¹ is CR¹⁹; n is 2;m is 0; and p is 0; wherein R¹⁹ is H, —OH, halogen, CN, —NH₂, or C₁-C₃alkyl. In some embodiments of the compounds of Formula I, II, IIa, IIb,III, and IIIa, L¹ is CR¹⁹; n is 2; m is 0; p is 0; and R¹⁹ is H.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, L¹ is N; n is 1; m is 1; and p is 0;wherein R²⁰ is —OR¹³, halogen, CN, —N(R¹³)₂, or C₁-C₃ alkyl; and eachR¹³ is independently H or C₁-C₃ alkyl. In some embodiments, L¹ is N; nis 1; m is 1; and p is 0; wherein R²⁰ is —OH, halogen, CN, —NH₂, orC₁-C₃ alkyl. In some embodiments, L is N; n is 1; m is 1; p is 0; andR²⁰ is C₁-C₃ alkyl. In some embodiments, L¹ is N; n is 1; m is 1; p is0; and R²⁰ is CH₃.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, L¹ is N; n is 0; m is 1; and p is 0;wherein R²⁰ is —OR¹³, halogen, CN, —N(R¹³)₂, and C₁-C₃ alkyl; and eachR¹³ is independently H or C₁-C₃ alkyl. In some embodiments, L¹ is N; nis 0; m is 1; and p is 0; and R²⁰ is —OH, halogen, CN, —NH₂, or C₁-C₃alkyl. In some embodiments, L is N; n is 0; m is 1; p is 0; and R²⁰ isC₁-C₃ alkyl. In some embodiments, L¹ is N; n is 0; m is 1; p is 0; andR²⁰ is CH₃.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, L¹ is N; n is 2; m is 1; and p is 0;wherein R²⁰ is —OR¹³, halogen, CN, —N(R¹³)₂, or C₁-C₃ alkyl; and eachR¹³ is independently H or C₁-C₃ alkyl. In some embodiments, L¹ is N; nis 2; m is 1; and p is 0; R²⁰ is —OH, halogen, CN, —NH₂, or C₁-C₃ alkyl.In some embodiments, L is N; n is 2; m is 1; p is 0; and R²⁰ is C₁-C₃alkyl. In some embodiments, L¹ is N; n is 1; m is 1; p is 0; and R²⁰ isCH₃.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, L is CR¹⁹; n is 1; m is 1; and p is 0;wherein R¹⁹ is H, —OR¹³, halogen, CN, —N(R¹³)₂, or C₁-C₃ alkyl; R²⁰ is—OR¹³, halogen, CN, —N(R¹³)₂, or C₁-C₃ alkyl; and each R¹³ isindependently H or C₁-C₃ alkyl. In some embodiments, L is CR¹⁹; n is 1;m is 1; and p is 0; wherein R¹⁹ is H, —OH, halogen, CN, —NH₂, or C₁-C₃alkyl; R²⁰ is —OH, halogen, CN, —NH₂, or C₁-C₃ alkyl. In someembodiments, L is CR¹⁹; n is 1; m is 1; and p is 0; wherein R¹⁹ is H andR²⁰ is —OH, halogen, CN, —NH₂, or C₁-C₃ alkyl. In some embodiments, L¹is CR¹⁹; n is 1; m is 1; and p is 0; wherein R¹⁹ is H and R²⁰ is C₁-C₃alkyl. In some embodiments, L¹ is CR¹⁹; n is 1; m is 1; p is 0; whereinR¹⁹ is H and R²⁰ is CH₃.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, L is CR¹⁹; n is 0; m is 1; and p is 0;wherein R¹⁹ is H, —OR¹³, halogen, CN, —N(R¹³)₂, or C₁-C₃ alkyl; R²⁰ is—OR¹³, halogen, CN, —N(R¹³)₂, or C₁-C₃ alkyl; and each R¹³ isindependently H or C₁-C₃ alkyl. In some embodiments, L is CR¹⁹; n is 0;m is 1; and p is 0; wherein R¹⁹ is H, —OH, halogen, CN, —NH₂, or C₁-C₃alkyl; R²⁰ is —OH, halogen, CN, —NH₂, or C₁-C₃ alkyl. In someembodiments, L is CR¹⁹; n is 0; m is 1; and p is 0; wherein R¹⁹ is H andR²⁰ is —OH, halogen, CN, —NH₂, or C₁-C₃ alkyl. In some embodiments, L¹is CR¹⁹; n is 0; m is 1; p is 0; R¹⁹ is H and R²⁰ is C₁-C₃ alkyl. Insome embodiments, L¹ is CR¹⁹; n is 0; m is 1; p is 0; R¹⁹ is H and R²⁰is CH₃.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, L is CR¹⁹; n is 2; m is 1; and p is 0;wherein R¹⁹ is H, —OR¹³, halogen, CN, —N(R¹³)₂, or C₁-C₃ alkyl; R²⁰ is—OR¹³, halogen, CN, —N(R¹³)₂, or C₁-C₃ alkyl; and each R¹³ isindependently H or C₁-C₃ alkyl. In some embodiments, L is CR¹⁹; n is 2;m is 1; and p is 0; wherein R¹⁹ is H, —OH, halogen, CN, —NH₂, or C₁-C₃alkyl; R²⁰ is —OH, halogen, CN, —NH₂, or C₁-C₃ alkyl. In someembodiments, L is CR¹⁹; n is 2; m is 1; and p is 0; wherein R¹⁹ is H andR²⁰ is —OH, halogen, CN, —NH₂, or C₁-C₃ alkyl. In some embodiments, L¹is CR¹⁹; n is 2; m is 1; p is 0; R¹⁹ is H and R²⁰ is C₁-C₃ alkyl. Insome embodiments, L is CR¹⁹; n is 2; m is 1; p is 0; R¹⁹ is H and R²⁰ isCH₃.

In some embodiments of the compounds of I, I-Z, I-E, II-Z, IIa-Z, IIb-Z,III-Z, and IIIa-Z, L¹ is CR¹⁹ or N; n is 0, 1, or 2; m is 0 or 1; and pis 0, 1, 2, or 3; wherein R¹⁹ is H, —OR¹³, halogen, CN, —N(R¹³)₂ orC₁-C₃ alkyl; R²⁰ is —OR¹³, halogen, CN, —N(R¹³)₂ or C₁-C₃ alkyl; eachR²¹ is independently —OR¹³, oxo, halogen, CN, —N(R¹³)₂ or C₁-C₃ alkyl;or two R²¹ groups on same or adjoining atoms are joined together to forma 3-6 membered carbocyclic ring or a 3-6 membered heterocyclic ring; andeach R¹³ is independently H or C₁-C₃ alkyl.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, L¹ is CR¹⁹ or N; n is 0, 1, or 2; m is0 or 1; and p is 0, 1, 2, or 3; wherein R¹⁹ is H; R²⁰ is —OR¹³, halogen,CN, —N(R¹³)₂, or C₁-C₃ alkyl; each R²¹ is independently —OR¹³, oxo,halogen, CN, —N(R¹³)₂ or C₁-C₃ alkyl; or two R²¹ groups on same oradjoining atoms are joined together to form a 3-6 membered carbocyclicring or a 3-6 membered heterocyclic ring; and each R¹³ is independentlyH or C₁-C₃ alkyl.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, L¹ is CR¹⁹ or N; n is 0, 1, or 2; m is0 or 1; and p is 0, 1, 2, or 3; wherein R¹⁹ is H; R²⁰ is C₁-C₃ alkyl;each R²¹ is independently —OR¹³, oxo, halogen, CN, —N(R¹³)₂ or C₁-C₃alkyl; or two R²¹ groups on same or adjoining atoms are joined togetherto form a 3-6 membered carbocyclic ring or a 3-6 membered heterocyclicring; and each R¹³ is independently H or C₁-C₃ alkyl.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, L¹ is CR¹⁹ or N; n is 0, 1, or 2; m is0; and p is 0, 1, 2, or 3; wherein R¹⁹ is H; each R²¹ is independently—OR¹³, oxo, halogen, CN, —N(R¹³)₂ or C₁-C₃ alkyl; or two R²¹ groups onsame or adjoining atoms are joined together to form a 3-6 memberedcarbocyclic ring or a 3-6 membered heterocyclic ring; and each R¹³ isindependently H or C₁-C₃ alkyl. In some embodiments, L is CR¹⁹ or N; nis 0, 1, or 2; m is 0; and p is 0, 1, 2, or 3; wherein R¹⁹ is H; andeach R²¹ is independently —OH, oxo, halogen, CN, —NH₂, or C₁-C₃ alkyl;or two R²¹ groups on same or adjoining atoms are joined together to forma 3-6 membered carbocyclic ring or a 3-6 membered heterocyclic ring.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, L¹ is CR¹⁹ or N; n is 0, 1, or 2; m is1; and p is 0, 1, 2, or 3; wherein R¹⁹ is H; R²⁰ is C₁-C₃ alkyl; andeach R²¹ is independently —OH, oxo, halogen, CN, —NH₂ or C₁-C₃ alkyl; ortwo R²¹ groups on same or adjoining atoms are joined together to form a3-6 membered carbocyclic ring or a 3-6 membered heterocyclic ring.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, L¹ is CR¹⁹ or N; n is 0, 1, or 2; m is1; and p is 0, 1, 2, or 3; wherein R¹⁹ is H; R²⁰ is CH₃; and each R²¹ isindependently —OH, oxo, halogen, CN, —NH₂ or C₁-C₃ alkyl; or two R²¹groups on same or adjoining atoms are joined together to form a 3-6membered carbocyclic ring or a 3-6 membered heterocyclic ring.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, L¹ is CR¹⁹ or N; n is 1; m is 0 or 1;and p is 0, 1, 2, or 3; wherein R¹⁹ is H, —OR¹³, halogen, CN, —N(R¹³)₂,or C₁-C₃ alkyl; R²⁰ is —OR¹³, halogen, CN, —N(R¹³)₂, or C₁-C₃ alkyl;each R²¹ is independently —OR¹³, oxo, halogen, CN, —N(R¹³)₂ or C₁-C₃alkyl; or two R²¹ groups on same or adjoining atoms are joined togetherto form a 3-6 membered carbocyclic ring or a 3-6 membered heterocyclicring; and each R¹³ is independently H or C₁-C₃ alkyl.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, L¹ is CR¹⁹ or N; n is 1; m is 0 or 1;and p is 0, 1, 2, or 3; wherein R¹⁹ is H; R²⁰ is —OR¹³, halogen, CN,—N(R¹³)₂, or C₁-C₃ alkyl; each R²¹ is independently —OR¹³, oxo, halogen,CN, —N(R¹³)₂ or C₁-C₃ alkyl; or two R²¹ groups on same or adjoiningatoms are joined together to form a 3-6 membered carbocyclic ring or a3-6 membered heterocyclic ring; and each R¹³ is independently H or C₁-C₃alkyl.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, L¹ is CR¹⁹ or N; n is 1; m is 0 or 1;and p is 0, 1, 2, or 3; wherein R¹⁹ is H; R²⁰ is C₁-C₃ alkyl; each R²¹is independently —OR¹³, oxo, halogen, CN, —N(R¹³)₂, or C₁-C₃ alkyl; ortwo R²¹ groups on same or adjoining atoms are joined together to form a3-6 membered carbocyclic ring or a 3-6 membered heterocyclic ring; andeach R¹³ is independently H or C₁-C₃ alkyl.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, L¹ is CR¹⁹ or N; n is 1; m is 0; and pis 0, 1, 2, or 3; wherein R¹⁹ is H; each R²¹ is independently —OR¹³,oxo, halogen, CN, —N(R¹³)₂ or C₁-C₃ alkyl; or two R²¹ groups on same oradjoining atoms are joined together to form a 3-6 membered carbocyclicring or a 3-6 membered heterocyclic ring; and each R¹³ is independentlyH or C₁-C₃ alkyl. In some embodiments, L is CR¹⁹ or N; n is 0, 1, or 2;m is 0; and p is 0, 1, 2, or 3; wherein R¹⁹ is H; and each R²¹ isindependently —OH, oxo, halogen, CN, —NH₂ or C₁-C₃ alkyl; or two R²¹groups on same or adjoining atoms are joined together to form a 3-6membered carbocyclic ring or a 3-6 membered heterocyclic ring.

In some embodiments of the compounds of the compounds of Formula I, I-Z,I-E, II-Z, IIa-Z, IIb-Z, III-Z, and IIIa-Z, L¹ is CR¹⁹ or N; n is 1; mis 1; and p is 0, 1, 2, or 3; wherein R¹⁹ is H; R²⁰ is C₁-C₃ alkyl; eachR²¹ is independently —OH, oxo, halogen, CN, —NH₂ or C₁-C₃ alkyl; or twoR²¹ groups on same or adjoining atoms are joined together to form a 3-6membered carbocyclic ring or a 3-6 membered heterocyclic ring.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, L¹ is CR¹⁹ or N; n is 1; m is 1; and pis 0, 1, 2, or 3; wherein R¹⁹ is H; R²⁰ is CH₃; each R²¹ isindependently —OH, oxo, halogen, CN, —NH₂, or C₁-C₃ alkyl; or two R²¹groups on same or adjoining atoms are joined together to form a 3-6membered carbocyclic ring or a 3-6 membered heterocyclic ring.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, L¹ is CR¹⁹ or N; n is 1; m is 1; and pis 0, 1, 2, or 3; wherein R¹⁹ is H, —OR¹³, halogen, CN, —N(R¹³)₂, orC₁-C₃ alkyl; R²⁰ is —OR¹³, halogen, CN, —N(R¹³)₂, or C₁-C₃ alkyl; eachR²¹ is independently —OR¹³, oxo, halogen, CN, —N(R¹³)₂ or C₁-C₃ alkyl;or two R²¹ groups on same or adjoining atoms are joined together toforma 3-6 membered carbocyclic ring or a 3-6 membered heterocyclic ring;and each R¹³ is independently H or C₁-C₃ alkyl.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, L¹ is CR¹⁹ or N; n is 0; m is 1; and pis 0, 1, 2, or 3; wherein R¹⁹ is H, —OR¹³, halogen, CN, —N(R¹³)₂, orC₁-C₃ alkyl; R²⁰ is —OR¹³, halogen, CN, —N(R¹³)₂, or C₁-C₃ alkyl; eachR²¹ is independently —OR¹³, oxo, halogen, CN, —N(R¹³)₂ or C₁-C₃ alkyl;or two R²¹ groups on same or adjoining atoms are joined together to forma 3-6 membered carbocyclic ring or a 3-6 membered heterocyclic ring; andeach R¹³ is independently H or C₁-C₃ alkyl.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, L¹ is CR¹⁹ or N; n is 2; m is 1; and pis 0, 1, 2, or 3; wherein R¹⁹ is H, —OR¹³, halogen, CN, —N(R¹³)₂, orC₁-C₃ alkyl; R²⁰ is —OR¹³, halogen, CN, —N(R¹³)₂, or C₁-C₃ alkyl; eachR²¹ is independently —OR¹³, oxo, halogen, CN, —N(R¹³)₂ or C₁-C₃ alkyl;or two R²¹ groups on same or adjoining atoms are joined together to forma 3-6 membered carbocyclic ring or a 3-6 membered heterocyclic ring; andeach R¹³ is independently H or C₁-C₃ alkyl.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, L¹ is CR¹⁹ or N; n is 1; m is 1; and pis 1; wherein R¹⁹ is H, —OR¹³, halogen, CN, —N(R¹³)₂ or C₁-C₃ alkyl; R²⁰is —OR¹³, halogen, CN, —N(R¹³)₂, or C₁-C₃ alkyl; R²¹ is independently—OR¹³, oxo, halogen, CN, —N(R¹³)₂ or C₁-C₃ alkyl; and each R¹³ isindependently H or C₁-C₃ alkyl. In some embodiments, L¹ is CR¹⁹ or N; nis 1; m is 1; and p is 1; wherein R¹⁹ is H; R²⁰ is —OR¹³, halogen, CN,—N(R¹³)₂, or C₁-C₃ alkyl; R²¹ is independently —OR¹³, oxo, halogen, CN,—N(R¹³)₂ or C₁-C₃ alkyl; and each R¹³ is independently H or C₁-C₃ alkyl.In some embodiments, L¹ is CR¹⁹ or N; n is 1; m is 1; and p is 1;wherein R¹⁹ is H; R²⁰ is C₁-C₃ alkyl; R²¹ is independently —OR¹³, oxo,halogen, CN, —N(R¹³)₂ or C₁-C₃ alkyl; and each R¹³ is independently H orC₁-C₃ alkyl. In some embodiments, L is CR¹⁹; n is 1; m is 1; and p is 1;wherein R¹⁹ is H; R²⁰ is CH₃; R²¹ is —OR¹³, oxo, halogen, CN, —N(R¹³)₂or C₁-C₃ alkyl; and each R¹³ is independently H or C₁-C₃ alkyl. In someembodiments, L is CR¹⁹; n is 1; m is 1; and p is 1; wherein R¹⁹ is H;R²⁰ is CH₃; R²¹ is —OH, oxo, halogen, CN, —NH₂ or C₁-C₃ alkyl. In someembodiments, L¹ is CR¹⁹; n is 1; m is 1; and p is 1; wherein R¹⁹ is H;R²⁰ is CH₃; and R²¹ is oxo.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, L¹ is N; n is 1; m is 1; and p is 1;R²⁰ is C₁-C₃ alkyl; R²¹ is —OR¹³, oxo, halogen, CN, —N(R¹³)₂ or C₁-C₃alkyl; and each R¹³ is independently H or C₁-C₃ alkyl. In someembodiments, L¹ is N; n is 1; m is 1; and p is 1; R²⁰ is CH₃; R²¹ is—OR¹³, oxo, halogen, CN, —N(R¹³)₂ or C₁-C₃ alkyl; and each R¹³ isindependently H or C₁-C₃ alkyl. In some embodiments, L¹ is N; n is 1; mis 1; and p is 1; wherein R²⁰ is CH₃; R²¹ is —OH, oxo, halogen, CN, —NH₂or C₁-C₃ alkyl. In some embodiments, L is N; n is 1; m is 1; and p is 1;wherein R²⁰ is CH₃; and R²¹ is oxo.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, L¹ is CR¹⁹ or N; n is 0; m is 1; and pis 0, 1, 2, or 3; wherein R¹⁹ is H, —OR¹³, halogen, CN, —N(R¹³)₂, orC₁-C₃ alkyl; R²⁰ is —OR¹³, halogen, CN, —N(R¹³)₂, or C₁-C₃ alkyl; eachR²¹ is independently —OR¹³, oxo, halogen, CN, —N(R¹³)₂ or C₁-C₃ alkyl;or two R²¹ groups on same or adjoining atoms are joined together to forma 3-6 membered carbocyclic ring or a 3-6 membered heterocyclic ring; andeach R¹³ is independently H or C₁-C₃ alkyl.

In some embodiments of the compounds of Formula II, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, L¹ is CR¹⁹ or N; n is 2; m is 1; and pis 0, 1, 2, or 3; wherein R¹⁹ is H, —OR¹³, halogen, CN, —N(R¹³)₂, orC₁-C₃ alkyl; R²⁰ is —OR¹³, halogen, CN, —N(R¹³)₂, or C₁-C₃ alkyl; eachR²¹ is independently —OR¹³, oxo, halogen, CN, —N(R¹³)₂ or C₁-C₃ alkyl;or two R²¹ groups on same or adjoining atoms are joined together to forma 3-6 membered carbocyclic ring or a 3-6 membered heterocyclic ring; andeach R¹³ is independently H or C₁-C₃ alkyl.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, m is 0 or 1; and p is 0, 1, 2, or 3. Insome embodiments, m is 0 or 1; p is 0, 1, 2, or 3; R²⁰ is C₁-C₃ alkyl;and each R²¹ is independently a halogen or oxo; or two R²¹ groups onsame atoms are joined together to form a 3-6 membered carbocyclic ringor a 3-6 membered heterocyclic ring having 1 or 2 heteroatoms selectedfrom N, O, and S.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, m is 0. In some embodiments, m is 1.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, R²⁰ is CH₃.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, p is 0.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, p is 2. In some embodiments, p is 2 andthe two R²¹ groups are on same atom and are joined together to form a3-6 membered carbocyclic ring or a 3-6 membered heterocyclic ring having1 or 2 heteroatoms selected from N, O, and S.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, m is 1; R²⁰ is C₁-C₃ alkyl; p is 2; andthe two R²¹ groups are on same atom and are joined together to form a3-6 membered carbocyclic ring.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, p is 1. In some embodiments, p is 1 andR²¹ is oxo.

In some embodiments of the compounds of Formula I, I-Z, I-E, II-Z,IIa-Z, IIb-Z, III-Z, and IIIa-Z, n is 0. In some embodiments, n is 1. Insome embodiments, n is 2.

In some embodiments, the compound of Formula I, I-Z, II-Z, IIa-Z, orIIb-Z, is selected from the group consisting of

In some embodiments, the compound of Formula I, I-Z, II-Z, IIa-Z, orIIb-Z is selected from the group consisting of

In some embodiments, the compound of Formula I, I-Z, or III-Z isselected from the group consisting of:

In some embodiments, the compound of Formula I, I-Z, III-Z, or IIIa-Z is

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula I, I-Z, III-Z, or IIIa-Z is

or a pharmaceutically acceptable salt thereof

In some embodiments, the compound of Formula I, I-Z, III-Z, or IIIa-Zis:

III. Compositions and Kits

Compounds provided herein are usually administered in the form ofpharmaceutical compositions. Thus, provided herein are alsopharmaceutical compositions that comprise one or more of the compoundsprovided herein or pharmaceutically acceptable salts, isomer, or amixture thereof and one or more pharmaceutically acceptable vehiclesselected from carriers, adjuvants and excipients. The compounds providedherein may be the sole active ingredient or one of the activeingredients of the pharmaceutical compositions. Suitablepharmaceutically acceptable vehicles may include, for example, inertsolid diluents and fillers, diluents, including sterile aqueous solutionand various organic solvents, permeation enhancers, solubilizers andadjuvants.

In one aspect, provided herein are pharmaceutical compositionscomprising a compound provided herein (e.g., a compound of Formula I,I-Z, I-E, II-Z, IIa-Z, IIb-Z, III-Z, and IIIa-Z), or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable excipient orcarrier. In some embodiments, the pharmaceutical compositions comprise atherapeutically effective amount of a compound provided herein, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient or carrier.

In some embodiments, the pharmaceutical compositions provided hereinfurther comprise one or more (e.g., one, two, three, four, one or two,one to three, or one to four) additional therapeutic agents, or apharmaceutically acceptable salt thereof.

In some embodiments, the one or more additional therapeutic agentsinclude agents that are therapeutic for a hepatitis B virus (HBV)infection, human immunodeficiency virus (HIV) infection, cancer, or ahyper-proliferative disease. In some embodiments, the one or moreadditional therapeutic agents include PD1 inhibitors and/or PDL1inhibitors. In some embodiments, the one or more additional therapeuticagents that are therapeutic for HBV infection include PDL1 inhibitorsand/or PDL1 inhibitors. In some embodiments, the one or more additionaltherapeutic agents that are therapeutic for cancer orhyper-proliferative disease include PD1 inhibitors and/or PDL1inhibitors.

In some embodiments, the one or more additional therapeutic agentsinclude agents that are therapeutic for HBV infection. In someembodiments, the one or more additional therapeutic agents is selectedfrom the group consisting of: adefovir (Hepsera®), tenofovir disoproxilfumarate+emtricitabine (Truvada®), tenofovir disoproxil fumarate(Viread®), entecavir (Baraclude®), lamivudine (Epivir-HBV®), tenofoviralafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamidefumarate, tenofovir alafenamide hemifumarate, telbivudine (Tyzeka®),Clevudine®, emtricitabine (Emtriva®), peginterferon alfa-2b(PEG-Intron®), Multiferon®, interferon alpha 1b (Hapgen®), interferonalpha-2b (Intron A®), pegylated interferon alpha-2a (Pegasys®),interferon alfa-n1 (Humoferon®), ribavirin, interferon beta-1a(Avonex®), Bioferon, Ingaron, Inmutag (Inferon), Algeron, Roferon-A,Oligotide, Zutectra, Shaferon, interferon alfa-2b (Axxo), Alfaferone,interferon alfa-2b, Feron, interferon-alpha 2 (CJ), Bevac, Laferonum,Vipeg, Blauferon-B, Blauferon-A, Intermax Alpha, Realdiron, Lanstion,Pegaferon, PDferon-B, alfainterferona 2b, Kalferon, Pegnano, Feronsure,PegiHep, Optipeg A, Realfa 2B, Reliferon, peginterferon alfa-2b,Reaferon-EC, Proquiferon, Uniferon, Urifron, interferon alfa-2b,Anterferon, Shanferon, MOR-22, interleukin-2 (IL-2), recombinant humaninterleukin-2 (Shenzhen Neptunus), Layfferon, Ka Shu Ning, Shang ShengLei Tai, Intefen, Sinogen, Fukangtai, Alloferon and celmoleukin, or apharmaceutically acceptable salt of any of the foregoing, or anycombinations thereof.

In some embodiments, the one or more additional therapeutic agentsinclude agents that are therapeutic for HIV infection. In someembodiments, the one or more additional therapeutic agents is selectedfrom the group consisting of 4′-ethynyl-2-fluoro-2′-deoxyadenosine,bictegravir or a pharmaceutically acceptable salt thereof, abacavirsulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate,tenofovir disoproxil hemifumarate, tenofovir alafenamide, tenofoviralafenamide hemifumarate, emtricitabine, and lamivudine, or apharmaceutically acceptable salt of any of the foregoing, or anycombinations thereof.

In some embodiments, the one or more additional therapeutic agentsinclude PD1 inhibitors and/or PDL1 inhibitors. In some embodiments, theone or more additional therapeutic agents is selected from the groupconsisting of nivolumab, lambrolizumab, pembrolizumab, pidilizumab,PDR001, TSR-001, atezolizumab, durvalumab, or avelumab, or apharmaceutically acceptable salt of any of the foregoing, or anycombinations thereof.

In some embodiments, the one or more additional therapeutic agentsinclude agents that are therapeutic for cancer or hyper-proliferativedisease. In some embodiments, the one or more additional therapeuticagents is selected from the group consisting of: rituxan, doxorubicin,gemcitabine, pidilizumab, TSR-042, BMS-986016, ruxolitinib,N-(cyanomethyl)-4-[2-(4-morpholinoanilino)pyrimidin-4-yl]benzamide,XL147, BKM120, GDC-0941, BAY80-6946, PX-866, CH5132799, XL756, BEZ235,and GDC-0980, wortmannin, LY294002, PI3K II, TGR-1202, AMG-319,GSK2269557, X-339, X-414, RP5090, KAR4141, XL499, OXY111A, IPI-145,IPI-443, GSK2636771, BAY 10824391, buparlisib, BYL719, RG7604, MLN1117,WX-037, AEZS-129, PA799, ZSTK474, AS252424, TGX221, TG100115, IC87114,IPI-549, INCB050465,(S)-2-(1-((9H-purin-6-yl)amino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,(S)-2-(1-((9H-purin-6-yl)amino)ethyl)-6-fluoro-3-phenylquinazolin-4(3H)-one,(S)-2-(1-((9H-purin-6-yl)amino)ethyl)-3-(2,6-difluorophenyl)quinazolin-4(3H)-one,(S)-4-amino-6-((1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile,and ipilimumab, or a pharmaceutically acceptable salt of any of theforegoing, or any combinations thereof.

In some embodiments, the one or more additional therapeutic agents isselected from the group consisting of idelalisib, tirabrutinib,momelotinib, and entospletinib, or a pharmaceutically acceptable salt ofany of the foregoing, or any combinations thereof.

The pharmaceutical compositions may be administered in either single ormultiple doses. The pharmaceutical compositions may be administered byvarious methods including, for example, rectal, buccal, intranasal andtransdermal routes. In some embodiments, the pharmaceutical compositionsmay be administered by intra-arterial injection, intravenously,intraperitoneally, parenterally, intramuscularly, subcutaneously,orally, topically, or as an inhalant.

One mode for administration is parenteral, for example, by injection.The forms in which the pharmaceutical compositions described herein maybe incorporated for administration by injection include, for example,aqueous or oil suspensions, or emulsions, with sesame oil, corn oil,cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose,or a sterile aqueous solution, and similar pharmaceutical vehicles.

Oral administration may be another route for administration of thecompounds provided herein. Administration may be via, for example,capsule or enteric coated tablets. In making the pharmaceuticalcompositions that include at least one compound provided herein orpharmaceutically acceptable salts, isomer, or a mixture thereof, theactive ingredient (such as a compound provided herein) is usuallydiluted by an excipient and/or enclosed within such a carrier that canbe in the form of a capsule, sachet, paper or other container. When theexcipient serves as a diluent, it can be in the form of a solid,semi-solid, or liquid material, which acts as a vehicle, carrier ormedium for the active ingredient. Thus, the pharmaceutical compositionscan be in the form of tablets, pills, powders, lozenges, sachets,cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols(as a solid or in a liquid medium), ointments containing, for example,up to 10% by weight of the active compound, soft and hard gelatincapsules, sterile injectable solutions, and sterile packaged powders.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose or any combinations thereof. The pharmaceutical compositionscan additionally include lubricating agents such as talc, magnesiumstearate, and mineral oil; wetting agents; emulsifying and suspendingagents; preserving agents such as methyl and propylhydroxy-benzoates;sweetening agents; and flavoring agents; or any combinations thereof.

The pharmaceutical compositions that include at least one compounddescribed herein or pharmaceutically acceptable salts, isomer, or amixture thereof can be formulated so as to provide quick, sustained ordelayed release of the active ingredient (such as a compound providedherein) after administration to the subject. Controlled release drugdelivery systems for oral administration include osmotic pump systemsand dissolutional systems containing polymer-coated reservoirs ordrug-polymer matrix formulations. Examples of controlled release systemsare given in U.S. Pat. Nos. 3,845,770; 4,326,525; 4,902,514; and5,616,345. Another formulation for use in the methods of the presentdisclosure employs transdermal delivery devices (“patches”). Suchtransdermal patches may be used to provide continuous or discontinuousinfusion of the compounds provided herein in controlled amounts.

For preparing solid compositions such as tablets, the principal activeingredient may be mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound described herein or pharmaceutically acceptable salts, isomer,or a mixture thereof. When referring to these preformulationcompositions as homogeneous, the active ingredient may be dispersedevenly throughout the composition so that the composition may be readilysubdivided into equally effective unit dosage forms such as tablets,pills and capsules.

The tablets or pills of the compounds described herein may be coated orotherwise compounded to provide a dosage form affording the advantage ofprolonged action, or to protect from the acid conditions of the stomach.For example, the tablet or pill can include an inner dosage and an outerdosage component, the latter being in the form of an envelope over theformer. The two components can be separated by an enteric layer thatserves to resist disintegration in the stomach and permit the innercomponent to pass intact into the duodenum or to be delayed in release.A variety of materials can be used for such enteric layers or coatings,such materials including a number of polymeric acids and mixtures ofpolymeric acids with materials such as shellac, cetyl alcohol, andcellulose acetate.

Pharmaceutical compositions for inhalation or insufflation may includesolutions and suspensions in pharmaceutically acceptable, aqueous ororganic solvents, or mixtures thereof, and powders. The liquid or solidcompositions may contain suitable pharmaceutically acceptable excipientsas described supra. In some embodiments, the compositions areadministered by the oral or nasal respiratory route for local orsystemic effect. In other embodiments, compositions in pharmaceuticallyacceptable solvents may be nebulized by use of inert gases. Nebulizedsolutions may be inhaled directly from the nebulizing device or thenebulizing device may be attached to a facemask tent, or intermittentpositive pressure breathing machine. Solution, suspension, or powdercompositions may be administered, preferably orally or nasally, fromdevices that deliver the formulation in an appropriate manner.

The compounds provided herein can be comprised in a kit. In one aspect,provided herein are kits that comprise a compound provided herein,(e.g., a compound of Formula I, I-Z, I-E, II-Z, IIa-Z, IIb-Z, III-Z, orIIIa-Z), or a pharmaceutically acceptable salt, stereoisomer, prodrug,or solvate thereof, and suitable packaging. In some embodiments, the kitfurther comprises instructions for use. In some embodiments, the kitcomprises a compound provided herein (e.g., a compound of Formula I,I-Z, I-E, II-Z, IIa-Z, IIb-Z, III-Z, or IIIa-Z), or a pharmaceuticallyacceptable salt, stereoisomer, prodrug, or solvate thereof, and a labeland/or instructions for use of the compounds in the treatment of theindications, including the diseases or conditions, described herein.

In some embodiments, the kits further comprise one or more (e.g., one,two, three, four, one or two, one to three, or one to four) additionaltherapeutic agents, or a pharmaceutically acceptable salt thereof.

In one aspect, provided herein are articles of manufacture that comprisea compound described herein or pharmaceutically acceptable salts,isomer, or a mixture thereof in a suitable container. In someembodiments, the container may be a vial, jar, ampoule, preloadedsyringe, or intravenous bag.

IV. Methods

The methods provided herein may be applied to cell populations in vivoor ex vivo. “In vivo” means within a living individual, as within ananimal or human. In this context, the methods provided herein may beused therapeutically in an individual. “Ex vivo” means outside of aliving individual. Examples of ex vivo cell populations include in vitrocell cultures and biological samples including fluid or tissue samplesobtained from individuals. Such samples may be obtained by suitablemethods. Exemplary biological fluid samples include blood, cerebrospinalfluid, urine, and saliva. Exemplary tissue samples include tumors andbiopsies thereof. In this context, the present disclosure may be usedfor a variety of purposes, including therapeutic and experimentalpurposes. For example, the present disclosure may be used ex vivo todetermine the optimal schedule and/or dosing of administration of a HPK1inhibitor for a given indication, cell type, individual, and otherparameters. Information gleaned from such use may be used forexperimental purposes or in the clinic to set protocols for in vivotreatment. Other ex vivo uses for which the present disclosure may besuited are described below or will become apparent to those skilled inthe art. The selected compounds may be further characterized to examinethe safety or tolerance dosage in human or non-human subjects.

In one aspect, the present disclosure provides methods of inhibitingHPK1 activity in a subject in need thereof, comprising administering tothe subject a therapeutically effective amount of a compound providedherein (e.g., a compound of Formula I, I-Z, I-E, II-Z, IIa-Z, IIb-Z,III-Z, or IIIa-Z), or a pharmaceutically acceptable salt thereof, or apharmaceutical composition provided herein.

In one aspect, the present disclosure provides methods of treating adisease or disorder associated with increased HPK1 activity in a subjectin need thereof, comprising administering to the subject atherapeutically effective amount of a compound provided herein, or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition provided herein.

In one aspect, the present disclosure provides methods of increasingT-cell activation in a subject in need thereof, comprising administeringto the subject a therapeutically effective amount of a compound providedherein (e.g., a compound of Formula I, I-Z, I-E, II-Z, IIa-Z, IIb-Z,III-Z, or IIIa-Z), or a pharmaceutically acceptable salt thereof, or apharmaceutical composition provided herein.

In one aspect, the present disclosure provides methods of treatingcancer in a subject in need thereof, comprising administering to thesubject a therapeutically effective amount of a compound provided herein(e.g., a compound of Formula I, I-Z, I-E, II-Z, IIa-Z, IIb-Z, III-Z, orIIIa-Z), or a pharmaceutically acceptable salt thereof, or apharmaceutical composition provided herein.

In some embodiments, the cancer is selected from the group consisting ofbladder cancer, breast cancer, colorectal cancer, gastric cancer, headand neck squamous cell carcinoma, Hodgkin lymphoma, Merkel-cellcarcinoma, mesothelioma, melanoma, non-small cell lung cancer, lungcancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cellcarcinoma, small cell lung cancer, transitional cell carcinoma,urothelial cancer. In some embodiments, the cancer is a solid tumor.

In one aspect, the present disclosure provides methods of inhibiting thegrowth or proliferation of cancer cells in a subject in need thereof,comprising administering to the subject a therapeutically effectiveamount of a compound provided herein (e.g., a compound of Formula I,I-Z, I-E, II-Z, IIa-Z, IIb-Z, III-Z, or IIIa-Z), or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition providedherein.

In some embodiments, the above methods further comprise administering atherapeutically effective amount of one or more additional therapeuticagents, or a pharmaceutically acceptable salt thereof.

In some embodiments, the one or more additional therapeutic agents isselected from the group consisting of: Inducible T-cell costimulator(ICOS) agonists, cytotoxic T-lymphocyte antigen 4 (CTLA-4)-blockingantibodies, PD1 and/or PD-L1 inhibitors, Cluster of Differentiation 47(CD47) inhibitors, OX40 agonists, GITR agonists, CD27 agonists, CD28agonists, CD40 agonists, CD137 agonists, Toll-like receptor 8 (TLR8)agonists, T cell immunoglobulin and mucin domain-3 (TIM-3) inhibitors,lymphocyte activation gene 3 (LAG-3) inhibitors, CEACAM1 inhibitors, Tcell immunoreceptor with Ig and ITIM domains (TIGIT) inhibitors,V-domain immunoglobulin (Ig)-containing suppressor of T-cell activation(VISTA) inhibitors, anti-Killer IgG-like receptors (KIR) inhibitors,STING agonists, C-X-C chemokine receptor type 4 (CXCR-4) inhibitors,B7-H3 inhibitors, CD73 inhibitors, inhibitory RNA, IL2/15/17 fusionproteins, MKNK/2 inhibitors, JAK inhibitors, and PI3K inhibitors, or apharmaceutically acceptable salt of any of the foregoing, or anycombinations thereof.

In some embodiments, the one or more additional therapeutic agents isselected from the group consisting of: rituxan, doxorubicin,gemcitabine, nivolumab, pembrolizumab, pidilizumab, PDR001, TSR-001,atezolizumab, durvalumab, avelumab, pidilizumab, TSR-042, BMS-986016,ruxolitinib,N-(cyanomethyl)-4-[2-(4-morpholinoanilino)pyrimidin-4-yl]benzamide,XL147, BKM120, GDC-0941, BAY80-6946, PX-866, CH5132799, XL756, BEZ235,and GDC-0980, wortmannin, LY294002, PI3K II, TGR-1202, AMG-319,GSK2269557, X-339, X-414, RP5090, KAR4141, XL499, OXY111A, IPI-145,IPI-443, GSK2636771, BAY 10824391, buparlisib, BYL719, RG7604, MLN1117,WX-037, AEZS-129, PA799, ZSTK474, AS252424, TGX221, TG100115, IC87114,IPI-549, INCB050465,(S)-2-(1-((9H-purin-6-yl)amino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,(S)-2-(1-((9H-purin-6-yl)amino)ethyl)-6-fluoro-3-phenylquinazolin-4(3H)-one,(S)-2-(1-((9H-purin-6-yl)amino)ethyl)-3-(2,6-difluorophenyl)quinazolin-4(3H)-one,(S)-4-amino-6-((1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile,and ipilimumab, or a pharmaceutically acceptable salt of any of theforegoing, or any combinations thereof.

In some embodiments, the one or more additional therapeutic agents isselected from the group consisting of idelalisib, tirabrutinib,momelotinib, and entospletinib, or a pharmaceutically acceptable salt ofany of the foregoing, or any combinations thereof.

In one aspect, the present disclosure provides methods of treating orpreventing a hepatitis B virus (HBV) infection in a subject in needthereof, comprising administering to the subject a therapeuticallyeffective amount of a compound provided herein (e.g., a compound ofFormula I, I-Z, I-E, II-Z, IIa-Z, IIb-Z, III-Z, or IIIa-Z), or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition provided herein.

In some embodiments, the method of treating or preventing a HBVinfection further comprises administering a therapeutically effectiveamount of one or more additional therapeutic agents, or apharmaceutically acceptable salt thereof.

In some embodiments, the one or more additional therapeutic agents isselected from the group consisting of HBV combination drugs, HBVvaccines, HBV DNA polymerase inhibitors, immunomodulators, toll-likereceptor (TLR) modulators, interferon alpha receptor ligands,hyaluronidase inhibitors, hepatitis b surface antigen (HBsAg)inhibitors, cytotoxic T-lymphocyte-associated protein 4 (ipi4)inhibitors, cyclophilin inhibitors, HBV viral entry inhibitors,antisense oligonucleotide targeting viral mRNA, short interfering RNAs(siRNA) and ddRNAi endonuclease modulators, ribonucleotide reductaseinhibitors, HBV E antigen inhibitors, covalently closed circular DNA(cccDNA) inhibitors, farnesoid X receptor agonists, HBV antibodies, CCR2chemokine antagonists, thymosin agonists, cytokines, nucleoproteinmodulators, retinoic acid-inducible gene 1 stimulators, NOD2stimulators, phosphatidylinositol 3-kinase (PI3K) inhibitors,indoleamine-2,3-dioxygenase (IDO) pathway inhibitors, PD-1 inhibitors,PD-L1 inhibitors, recombinant thymosin alpha-1 agonists, Bruton'styrosine kinase (BTK) inhibitors, KDM inhibitors, HBV replicationinhibitors, arginase inhibitors, and other HBV drugs, or apharmaceutically acceptable salt of any of the foregoing, or anycombinations thereof.

In some embodiments, the one or more additional therapeutic agents isselected from the group consisting of adefovir (Hepsera®), tenofovirdisoproxil fumarate+emtricitabine (Truvada®), tenofovir disoproxilfumarate (Viread®), entecavir (Baraclude®), lamivudine (Epivir-HBV®),tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofoviralafenamide fumarate, tenofovir alafenamide hemifumarate, telbivudine(Tyzeka®), Clevudine®, emtricitabine (Emtriva®), peginterferon alfa-2b(PEG-Intron®), Multiferon®, interferon alpha 1b (Hapgen®), interferonalpha-2b (Intron A®), pegylated interferon alpha-2a (Pegasys®),interferon alfa-n1 (Humoferon®), ribavirin, interferon beta-1a(Avonex®), Bioferon, Ingaron, Inmutag (Inferon), Algeron, Roferon-A,Oligotide, Zutectra, Shaferon, interferon alfa-2b (Axxo), Alfaferone,interferon alfa-2b, Feron, interferon-alpha 2 (CJ), Bevac, Laferonum,Vipeg, Blauferon-B, Blauferon-A, Intermax Alpha, Realdiron, Lanstion,Pegaferon, PDferon-B, alfainterferona 2b, Kalferon, Pegnano, Feronsure,PegiHep, Optipeg A, Realfa 2B, Reliferon, peginterferon alfa-2b,Reaferon-EC, Proquiferon, Uniferon, Urifron, interferon alfa-2b,Anterferon, Shanferon, MOR-22, interleukin-2 (IL-2), recombinant humaninterleukin-2 (Shenzhen Neptunus), Layfferon, Ka Shu Ning, Shang ShengLei Tai, Intefen, Sinogen, Fukangtai, Alloferon and celmoleukin, or apharmaceutically acceptable salt of any of the foregoing, or anycombinations thereof.

In some embodiments, the one or more additional therapeutic agents isselected from the group consisting of entecavir, adefovir, tenofovirdisoproxil fumarate, tenofovir alafenamide, tenofovir, tenofovirdisoproxil, tenofovir alafenamide fumarate, tenofovir alafenamidehemifumarate, telbivudine and lamivudine, or a pharmaceuticallyacceptable salt of any of the foregoing, or any combinations thereof.

In some embodiments, the one or more additional therapeutic agents isselected from the group consisting of tenofovir alafenamide, tenofoviralafenamide fumarate, and tenofovir alafenamide hemifumarate, or apharmaceutically acceptable salt of any of the foregoing, or anycombinations thereof.

In one aspect, the present disclosure provides methods of treating orpreventing a human immunodeficiency virus (HIV) infection in a subjectin need thereof, comprising administering to the subject atherapeutically effective amount of a compound provided herein (e.g., acompound of Formula I, I-Z, I-E, II-Z, IIa-Z, IIb-Z, III-Z, or IIIa-Z),or a pharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition provided herein.

In some embodiments, the method of treating or preventing a HIVinfection further comprises administering a therapeutically effectiveamount of one or more additional therapeutic agents, or apharmaceutically acceptable salt thereof.

In some embodiments, the one or more additional therapeutic agents isselected from the group consisting of: combination drugs for HIV, otherdrugs for treating HIV, HIV protease inhibitors, HIV non-nucleoside ornon-nucleotide inhibitors of reverse transcriptase, HIV nucleoside ornucleotide inhibitors of reverse transcriptase, HIV integraseinhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors,HIV entry inhibitors, HIV maturation inhibitors, latency reversingagents, compounds that target the HIV capsid, immune-based therapies,phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies,bispecific antibodies and “antibody-like” therapeutic proteins, HIV p17matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-transisomerase A modulators, protein disulfide isomerase inhibitors,complement C₅a receptor antagonists, DNA methyltransferase inhibitor,HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viralinfectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nefmodulators, Hck tyrosine kinase modulators, mixed lineage kinase-3(MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors,integrin antagonists, nucleoprotein inhibitors, splicing factormodulators, COMM domain containing protein 1 modulators, HIVribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors,dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAG proteininhibitors, HIV POL protein inhibitors, Complement Factor H modulators,ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclindependent kinase inhibitors, proprotein convertase PC9 stimulators, ATPdependent RNA helicase DDX3X inhibitors, reverse transcriptase primingcomplex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokineticenhancers, HIV gene therapy, and HIV vaccines, or a pharmaceuticallyacceptable salt of any of the foregoing, or any combinations thereof.

In some embodiments, the one or more additional therapeutic agents isselected from the group consisting of HIV protease inhibiting compounds,HIV non-nucleoside inhibitors of reverse transcriptase, HIVnon-nucleotide inhibitors of reverse transcriptase, HIV nucleosideinhibitors of reverse transcriptase, HIV nucleotide inhibitors ofreverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerizationinhibitors, pharmacokinetic enhancers, and other drugs for treating HIV,or a pharmaceutically acceptable salt of any of the foregoing, or anycombinations thereof.

In some embodiments, the one or more additional therapeutic agents isselected from the group consisting of4′-ethynyl-2-fluoro-2′-deoxyadenosine, bictegravir, abacavir sulfate,tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate,tenofovir disoproxil hemifumarate, tenofovir alafenamide, and tenofoviralafenamide hemifumarate, or a pharmaceutically acceptable salt of anyof the foregoing, or any combinations thereof.

In some embodiments, the one or more additional therapeutic agents isselected from the group consisting of4′-ethynyl-2-fluoro-2′-deoxyadenosine, bictegravir, tenofoviralafenamide, tenofovir alafenamide fumarate and tenofovir alafenamidehemifumarate, or a pharmaceutically acceptable salt of any of theforegoing, or any combinations thereof.

In some embodiments, the one or more additional therapeutic agents isselected from the group consisting of4′-ethynyl-2-fluoro-2′-deoxyadenosine, bictegravir, tenofovirdisoproxil, tenofovir disoproxil hemifumarate, and tenofovir disoproxilfumarate, or a pharmaceutically acceptable salt of any of the foregoing,or any combinations thereof.

In some embodiments, the one or more additional therapeutic agents isselected from the group consisting of emtricitabine and lamivudine, or apharmaceutically acceptable salt of each thereof.

In some embodiments, the one or more additional therapeutic agents isemtricitabine or a pharmaceutically acceptable salt thereof.

In some embodiments, the method of treating or preventing a HIVinfection further comprises administering one or more additionaltherapeutic agents selected from the group consisting of4′-ethynyl-2-fluoro-2′-deoxyadenosine, bictegravir, tenofovir, tenofovirdisoproxil, tenofovir disoproxil fumarate, tenofovir disoproxilhemifumarate, tenofovir alafenamide, and tenofovir alafenamidehemifumarate, or a pharmaceutically acceptable salt of any of theforegoing, or any combinations thereof, and further comprisesadministering another therapeutic agent selected from the groupconsisting of emtricitabine and lamivudine, or a pharmaceuticallyacceptable salt of each thereof.

In some embodiments, the method of treating or preventing a HIVinfection further comprises administering one or more additionaltherapeutic agents selected from the group consisting of4′-ethynyl-2-fluoro-2′-deoxyadenosine, bictegravir, tenofoviralafenamide, and tenofovir alafenamide hemifumarate, or apharmaceutically acceptable salt of any of the foregoing, or anycombinations thereof, and further comprises administering anothertherapeutic agent selected from the group consisting of emtricitabineand lamivudine, or a pharmaceutically acceptable salt of each thereof.

In some embodiments, the method of treating or preventing a HIVinfection further comprises administering one or more additionaltherapeutic agents selected from the group consisting of4′-ethynyl-2-fluoro-2′-deoxyadenosine, bictegravir, tenofovirdisoproxil, tenofovir disoproxil fumarate, and tenofovir disoproxilhemifumarate, or a pharmaceutically acceptable salt of any of theforegoing, or any combinations thereof, and further comprisesadministering another therapeutic agent selected from the groupconsisting of emtricitabine and lamivudine, or a pharmaceuticallyacceptable salt thereof.

In some embodiments, the methods described herein comprise administeringa therapeutically effective amount of a compound provided herein (e.g.,a compound of Formula I, I, I-Z, I-E, II-Z, IIa-Z, IIb-Z, III-Z, orIIIa-Z), or a pharmaceutically acceptable salt thereof. In someembodiments, the methods described herein comprise administering atherapeutically effective amount of a pharmaceutical compositionprovided herein.

In one aspect, provided herein is a compound disclosed herein, or apharmaceutically acceptable salt thereof, for use in therapy.

In one aspect, provided herein is a compound disclosed herein, or apharmaceutically acceptable salt thereof, for use in a method ofinhibiting hematopoietic progenitor kinase 1 (HPK1) activity in asubject in need thereof.

In one aspect, provided herein is a compound disclosed herein, or apharmaceutically acceptable salt thereof, for use in a method oftreating a disease or disorder associated with increased hematopoieticprogenitor kinase 1 (HPK1) activity in a subject in need thereof.

In one aspect, provided herein is a compound disclosed herein, or apharmaceutically acceptable salt thereof, for use in a method ofincreasing T-cell activation in a subject in need thereof.

In one aspect, provided herein is a compound disclosed herein, or apharmaceutically acceptable salt thereof, for use in a method oftreating cancer in a subject in need thereof.

In some embodiments, the cancer is selected from the group consisting ofbladder cancer, breast cancer, colorectal cancer, gastric cancer, headand neck squamous cell carcinoma, Hodgkin lymphoma, Merkel-cellcarcinoma, mesothelioma, melanoma, non-small cell lung cancer, lungcancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cellcarcinoma, small cell lung cancer, transitional cell carcinoma, andurothelial cancer. In some embodiments, the cancer is a solid tumor.

In one aspect, provided herein is a compound disclosed herein, or apharmaceutically acceptable salt thereof, for use in a method ofinhibiting the growth or proliferation of cancer cells in a subject inneed thereof.

In some embodiments, the use in a method of inhibiting the growth orproliferation of cancer cells in a subject in need thereof furthercomprises administering a therapeutically effective amount of one ormore additional therapeutic agents, or a pharmaceutically acceptablesalt thereof.

In some embodiments, the use in a method of inhibiting the growth orproliferation of cancer cells in a subject in need thereof furthercomprises administering one or more additional therapeutic agentsselected from the group consisting of Inducible T-cell costimulator(ICOS) agonists, cytotoxic T-lymphocyte antigen 4 (CTLA-4)-blockingantibodies, PD1 and/or PD-L1 inhibitors, Cluster of Differentiation 47(CD47) inhibitors, OX40 agonists, GITR agonists, CD27 agonists, CD28agonists, CD40 agonists, CD137 agonists, Toll-like receptor 8 (TLR8)agonists, T cell immunoglobulin and mucin domain-3 (TIM-3) inhibitors,lymphocyte activation gene 3 (LAG-3) inhibitors, CEACAM1 inhibitors, Tcell immunoreceptor with Ig and ITIM domains (TIGIT) inhibitors,V-domain immunoglobulin (Ig)-containing suppressor of T-cell activation(VISTA) inhibitors, anti-Killer IgG-like receptors (KIR) inhibitors,STING agonists, C-X-C chemokine receptor type 4 (CXCR-4) inhibitors,B7-H3 inhibitors, CD73 inhibitors, inhibitory RNA, IL2/15/17 fusionproteins, MKNK1/2 inhibitors, JAK inhibitors, and PI3K inhibitors, or apharmaceutically acceptable salt of any of the foregoing, or anycombinations thereof.

In some embodiments, the use in a method of inhibiting the growth orproliferation of cancer cells in a subject in need thereof furthercomprises administering one or more additional therapeutic agentsselected from the group consisting of: rituxan, doxorubicin,gemcitabine, nivolumab, pembrolizumab, pidilizumab, PDR001, TSR-001,atezolizumab, durvalumab, avelumab, pidilizumab, TSR-042, BMS-986016,ruxolitinib,N-(cyanomethyl)-4-[2-(4-morpholinoanilino)pyrimidin-4-yl]benzamide,XL147, BKM120, GDC-0941, BAY80-6946, PX-866, CH5132799, XL756, BEZ235,and GDC-0980, wortmannin, LY294002, TGR-1202, AMG-319, GSK2269557,X-339, X-414, RP5090, KAR4141, XL499, OXY111A, IPI-145, IPI-443,GSK2636771, BAY 10824391, buparlisib, BYL719, RG7604, MLN1117, WX-037,AEZS-129, PA799, ZSTK474, AS252424, TGX221, TG100115, IC87114, IPI-549,INCB050465,(S)-2-(1-((9H-purin-6-yl)amino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,(S)-2-(1-((9H-purin-6-yl)amino)ethyl)-6-fluoro-3-phenylquinazolin-4(3H)-one,(S)-2-(1-((9H-purin-6-yl)amino)ethyl)-3-(2,6-difluorophenyl)quinazolin-4(3H)-one,(S)-4-amino-6-((1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile,and ipilimumab, or a pharmaceutically acceptable salt of any of theforegoing, or any combinations thereof.

In some embodiments, the use in a method of inhibiting the growth orproliferation of cancer cells in a subject in need thereof furthercomprises administering one or more additional therapeutic agentsselected from the group consisting of idelalisib, tirabrutinib,momelotinib, and entospletinib, or a pharmaceutically acceptable salt ofany of the foregoing, or any combinations thereof.

In one aspect, provided herein is a compound disclosed herein, or apharmaceutically acceptable salt thereof, for use in a method oftreating or preventing a hepatitis B virus (HBV) infection in a subjectin need thereof.

In some embodiments, the use in a method of treating or preventing ahepatitis B virus (HBV) infection in a subject in need thereof furthercomprises administering a therapeutically effective amount of one ormore additional therapeutic agents, or a pharmaceutically acceptablethereof.

In some embodiments, the use in a method of treating or preventing ahepatitis B virus (HBV) infection in a subject in need thereof furthercomprises administering one or more additional therapeutic agentsselected from the group consisting of HBV combination drugs, HBVvaccines, HBV DNA polymerase inhibitors, immunomodulators, toll-likereceptor (TLR) modulators, interferon alpha receptor ligands,hyaluronidase inhibitors, hepatitis b surface antigen (HBsAg)inhibitors, cytotoxic T-lymphocyte-associated protein 4 (ipi4)inhibitors, cyclophilin inhibitors, HBV viral entry inhibitors,antisense oligonucleotide targeting viral mRNA, short interfering RNAs(siRNA) and ddRNAi endonuclease modulators, ribonucelotide reductaseinhibitors, HBV E antigen inhibitors, covalently closed circular DNA(cccDNA) inhibitors, farnesoid X receptor agonists, HBV antibodies, CCR2chemokine antagonists, thymosin agonists, cytokines, nucleoproteinmodulators, retinoic acid-inducible gene 1 stimulators, NOD2stimulators, phosphatidylinositol 3-kinase (PI3K) inhibitors,indoleamine-2,3-dioxygenase (IDO) pathway inhibitors, PD-1 inhibitors,PD-L1 inhibitors, recombinant thymosin alpha-1 agonists, Bruton'styrosine kinase (BTK) inhibitors, KDM inhibitors, HBV replicationinhibitors, arginase inhibitors, and other HBV drugs, or apharmaceutically acceptable salt of any of the foregoing, or anycombinations thereof.

In some embodiments, the use in a method of treating or preventing ahepatitis B virus (HBV) infection in a subject in need thereof furthercomprises administering one or more additional therapeutic agentsselected from the group consisting of adefovir (Hepsera®), tenofovirdisoproxil fumarate+emtricitabine (Truvada®), tenofovir disoproxilfumarate (Viread®), entecavir (Baraclude®), lamivudine (Epivir-HBV®),tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofoviralafenamide fumarate, tenofovir alafenamide hemifumarate, telbivudine(Tyzeka®), Clevudine®, emtricitabine (Emtriva®), peginterferon alfa-2b(PEG-Intron®), Multiferon®, interferon alpha 1b (Hapgen®), interferonalpha-2b (Intron A®), pegylated interferon alpha-2a (Pegasys®),interferon alfa-n (Humoferon®), ribavirin, interferon beta-1a (Avonex®),Bioferon, Ingaron, Inmutag (Inferon), Algeron, Roferon-A, Oligotide,Zutectra, Shaferon, interferon alfa-2b (Axxo), Alfaferone, interferonalfa-2b, Feron, interferon-alpha 2 (CJ), Bevac, Laferonum, Vipeg,Blauferon-B, Blauferon-A, Intermax Alpha, Realdiron, Lanstion,Pegaferon, PDferon-B, alfainterferona 2b, Kalferon, Pegnano, Feronsure,PegiHep, Optipeg A, Realfa 2B, Reliferon, peginterferon alfa-2b,Reaferon-EC, Proquiferon, Uniferon, Urifron, interferon alfa-2b,Anterferon, Shanferon, MOR-22, interleukin-2 (IL-2), recombinant humaninterleukin-2 (Shenzhen Neptunus), Layfferon, Ka Shu Ning, Shang ShengLei Tai, Intefen, Sinogen, Fukangtai, Alloferon and celmoleukin, or apharmaceutically acceptable salt of any of the foregoing, or anycombinations thereof.

In some embodiments, the use in a method of treating or preventing ahepatitis B virus (HBV) infection in a subject in need thereof furthercomprises administering one or more additional therapeutic agentsselected from the group consisting of entecavir, adefovir, tenofovirdisoproxil fumarate, tenofovir alafenamide, tenofovir, tenofovirdisoproxil, tenofovir alafenamide fumarate, tenofovir alafenamidehemifumarate, telbivudine and lamivudine, or a pharmaceuticallyacceptable salt of any of the foregoing, or any combinations thereof.

In some embodiments, the use in a method of treating or preventing ahepatitis B virus (HBV) infection in a subject in need thereof furthercomprises administering one or more additional therapeutic agentsselected from the group consisting of tenofovir alafenamide, tenofoviralafenamide fumarate, and tenofovir alafenamide hemifumarate, or apharmaceutically acceptable salt of any of the foregoing, or anycombinations thereof.

In one aspect, provided herein is a compound disclosed herein, or apharmaceutically acceptable salt thereof, for use in a method oftreating or preventing a human immunodeficiency virus (HIV) infection ina subject in need thereof.

In some embodiments, the use in a method of treating or preventing ahepatitis B virus (HBV) infection in a subject in need thereof furthercomprises administering one or more additional therapeutic agents, or apharmaceutically acceptable salt thereof.

In some embodiments, the use in a method of treating or preventing ahepatitis B virus (HBV) infection in a subject in need thereof furthercomprises administering one or more additional therapeutic agentsselected from the group consisting of: combination drugs for HIV, otherdrugs for treating HIV, HIV protease inhibitors, HIV non-nucleoside ornon-nucleotide inhibitors of reverse transcriptase, HIV nucleoside ornucleotide inhibitors of reverse transcriptase, HIV integraseinhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors,HIV entry inhibitors, HIV maturation inhibitors, latency reversingagents, compounds that target the HIV capsid, immune-based therapies,phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies,bispecific antibodies and “antibody-like” therapeutic proteins, HIV p17matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-transisomerase A modulators, protein disulfide isomerase inhibitors,complement C₅a receptor antagonists, DNA methyltransferase inhibitor,HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viralinfectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nefmodulators, Hck tyrosine kinase modulators, mixed lineage kinase-3(MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors,integrin antagonists, nucleoprotein inhibitors, splicing factormodulators, COMM domain containing protein 1 modulators, HIVribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors,dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAG proteininhibitors, HIV POL protein inhibitors, Complement Factor H modulators,ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclindependent kinase inhibitors, proprotein convertase PC9 stimulators, ATPdependent RNA helicase DDX3X inhibitors, reverse transcriptase primingcomplex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokineticenhancers, HIV gene therapy, and HIV vaccines, or a pharmaceuticallyacceptable salt of any of the foregoing, or any combinations thereof.

In some embodiments, the use in a method of treating or preventing ahepatitis B virus (HBV) infection in a subject in need thereof furthercomprises administering one or more additional therapeutic agentsselected from the group consisting of HIV protease inhibiting compounds,HIV non-nucleoside inhibitors of reverse transcriptase, HIVnon-nucleotide inhibitors of reverse transcriptase, HIV nucleosideinhibitors of reverse transcriptase, HIV nucleotide inhibitors ofreverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerizationinhibitors, pharmacokinetic enhancers, and other drugs for treating HIV,or a pharmaceutically acceptable salt of any of the foregoing, or anycombinations thereof.

In some embodiments, the use in a method of treating or preventing ahepatitis B virus (HBV) infection in a subject in need thereof furthercomprises administering one or more additional therapeutic agentsselected from the group consisting of4′-ethynyl-2-fluoro-2′-deoxyadenosine, bictegravir, abacavir sulfate,tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate,tenofovir disoproxil hemifumarate, tenofovir alafenamide, and tenofoviralafenamide hemifumarate, or a pharmaceutically acceptable salt of anyof the foregoing, or any combinations thereof.

In some embodiments, the use in a method of treating or preventing ahepatitis B virus (HBV) infection in a subject in need thereof furthercomprises administering one or more additional therapeutic agentsselected from the group consisting of4′-ethynyl-2-fluoro-2′-deoxyadenosine, bictegravir, tenofoviralafenamide, tenofovir alafenamide fumarate or tenofovir alafenamidehemifumarate, or a pharmaceutically acceptable salt of any of theforegoing, or any combinations thereof.

In some embodiments, the use in a method of treating or preventing ahepatitis B virus (HBV) infection in a subject in need thereof furthercomprises administering one or more additional therapeutic agentsselected from the group consisting of4′-ethynyl-2-fluoro-2′-deoxyadenosine, bictegravir or a pharmaceuticallyacceptable salt thereof, tenofovir disoproxil, tenofovir disoproxilhemifumarate or tenofovir disoproxil fumarate, or a pharmaceuticallyacceptable salt of any of the foregoing, or any combinations thereof.

In some embodiments, the uses described herein comprise administering atherapeutically effective amount of a compound provided herein (e.g., acompound of Formula I, I-Z, I-E, II-Z, IIa-Z, IIb-Z, III-Z, or IIIa-Z),or a pharmaceutically acceptable salt thereof.

V. Administration

The compounds of the present disclosure (also referred to herein as theactive ingredients), can be administered by any route appropriate to thecondition to be treated. Suitable routes include oral, rectal, nasal,topical (including buccal and sublingual), transdermal, vaginal andparenteral (including subcutaneous, intramuscular, intravenous,intradermal, intrathecal and epidural), and the like. It will beappreciated that the preferred route may vary with, for example, thecondition of the recipient. An advantage of certain compounds disclosedherein is that they are orally bioavailable and can be dosed orally.

A compound of the present disclosure may be administered to anindividual in accordance with an effective dosing regimen for a desiredperiod of time or duration, such as at least about one month, at leastabout 2 months, at least about 3 months, at least about 6 months, or atleast about 12 months or longer. In some embodiments, the compound isadministered on a daily or intermittent schedule for the duration of theindividual's life.

The specific dose level of a compound of the present disclosure for anyparticular subject will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease in the subject undergoing therapy. Forexample, a dosage may be expressed as a number of milligrams of acompound described herein per kilogram of the subject's body weight(mg/kg). Dosages of between about 0.1 and 1000 mg/kg, for example,between about 0.1 and 700 mg/kg, between about 0.1 and 500 mg/kg,between about 0.1 and 300 mg/Kg or between about 0.1 and 150 mg/kg maybe appropriate. In some embodiments, about 0.1 and 100 mg/kg may beappropriate. In other embodiments a dosage of between 0.5 and 60 mg/kgmay be appropriate. Normalizing according to the subject's body weightis particularly useful when adjusting dosages between subjects of widelydisparate size, such as occurs when using the drug in both children andadult humans or when converting an effective dosage in a non-humansubject such as dog to a dosage suitable for a human subject.

The daily dosage may also be described as a total amount of a compounddescribed herein administered per dose or per day. Daily dosage of acompound of Formula I, I-Z, I-E, II-Z, IIa-Z, IIb-Z, III-Z, or IIIa-Z,or a pharmaceutically acceptable salt or pharmaceutically acceptabletautomer thereof, may be between about 1 mg and 4,000 mg, between about2,000 to 4,000 mg/day, between about 1 to 2,000 mg/day, between about 1to 1,000 mg/day, between about 10 to 500 mg/day, between about 20 to 500mg/day, between about 50 to 300 mg/day, between about 75 to 200 mg/day,or between about 15 to 150 mg/day.

The dosage or dosing frequency of a compound of the present disclosuremay be adjusted over the course of the treatment, based on the judgmentof the administering physician.

The compounds of the present disclosure may be administered to anindividual (e.g., a human) in a therapeutically effective amount. Insome embodiments, the compound is administered once daily.

The compounds provided herein can be administered by any useful routeand means, such as by oral or parenteral (e.g., intravenous)administration. Therapeutically effective amounts of the compound mayinclude from about 0.00001 mg/kg body weight per day to about 10 mg/kgbody weight per day, such as from about 0.0001 mg/kg body weight per dayto about 10 mg/kg body weight per day, or such as from about 0.001 mg/kgbody weight per day to about 1 mg/kg body weight per day, or such asfrom about 0.01 mg/kg body weight per day to about 1 mg/kg body weightper day, or such as from about 0.05 mg/kg body weight per day to about0.5 mg/kg body weight per day. In some embodiments, a therapeuticallyeffective amount of the compounds provided herein include from about 0.3mg to about 30 mg per day, or from about 30 mg to about 300 mg per day,or from about 0.3 g to about 30 mg per day, or from about 30 μg to about300 g per day.

A compound of the present disclosure may be combined with one or moreadditional therapeutic agents in any dosage amount of the compound ofthe present disclosure (e.g., from 1 mg to 1000 mg of compound).Therapeutically effective amounts may include from about 0.1 mg per doseto about 1000 mg per dose, such as from about 50 mg per dose to about500 mg per dose, or such as from about 100 mg per dose to about 400 mgper dose, or such as from about 150 mg per dose to about 350 mg perdose, or such as from about 200 mg per dose to about 300 mg per dose, orsuch as from about 0.01 mg per dose to about 1000 mg per dose, or suchas from about 0.01 mg per dose to about 100 mg per dose, or such as fromabout 0.1 mg per dose to about 100 mg per dose, or such as from about 1mg per dose to about 100 mg per dose, or such as from about 1 mg perdose to about 10 mg per dose, or such as from about 1 mg per dose toabout 1000 mg per dose. Other therapeutically effective amounts of thecompound of Formula I, I-Z, I-E, II-Z, IIa-Z, IIb-Z, III-Z, or IIIa-Zare about 1 mg per dose, or about 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20,25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or about 100mg per dose. Other therapeutically effective amounts of the compound ofthe present disclosure are about 100, 125, 150, 175, 200, 225, 250, 275,300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625,650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, orabout 1000 mg per dose.

In some embodiments, the methods described herein comprise administeringto the subject an initial daily dose of about 1 to 500 mg of a compoundprovided herein and increasing the dose by increments until clinicalefficacy is achieved. Increments of about 5, 10, 25, 50, or 100 mg canbe used to increase the dose. The dosage can be increased daily, everyother day, twice per week, once per week, once every two weeks, onceevery three weeks, or once a month.

When administered orally, the total daily dosage for a human subject maybe between about 1 mg and 1,000 mg, between about 10-500 mg/day, betweenabout 50-300 mg/day, between about 75-200 mg/day, or between about100-150 mg/day. In some embodiments, the total daily dosage for a humansubject may be about 100, 200, 300, 400, 500, 600, 700, 800, 900, or1000 mg/day administered in a single dose. In some embodiments, thetotal daily dosage for a human subject may be about 200, 300, 400, 500,600, 700, or 800 mg/day administered in a single dose. In someembodiments, the total daily dosage for a human subject may be about300, 400, 500, or 600 mg/day administered in a single dose.

In some embodiments, the total daily dosage for a human subject may beabout 100 mg/day administered in a single dose. In some embodiments, thetotal daily dosage for a human subject may be about 150 mg/dayadministered in a single dose. In some embodiments, the total dailydosage for a human subject may be about 200 mg/day administered in asingle dose. In some embodiments, the total daily dosage for a humansubject may be about 250 mg/day administered in a single dose. In someembodiments, the total daily dosage for a human subject may be about 300mg/day administered in a single dose. In some embodiments, the totaldaily dosage for a human subject may be about 350 mg/day administered ina single dose. In some embodiments, the total daily dosage for a humansubject may be about 400 mg/day administered in a single dose. In someembodiments, the total daily dosage for a human subject may be about 450mg/day administered in a single dose. In some embodiments, the totaldaily dosage for a human subject may be about 500 mg/day administered ina single dose. In some embodiments, the total daily dosage for a humansubject may be about 550 mg/day administered in a single dose. In someembodiments, the total daily dosage for a human subject may be about 600mg/day administered in a single dose. In some embodiments, the totaldaily dosage for a human subject may be about 650 mg/day administered ina single dose. In some embodiments, the total daily dosage for a humansubject may be about 700 mg/day administered in a single dose. In someembodiments, the total daily dosage for a human subject may be about 750mg/day administered in a single dose. In some embodiments, the totaldaily dosage for a human subject may be about 800 mg/day administered ina single dose. In some embodiments, the total daily dosage for a humansubject may be about 850 mg/day administered in a single dose. In someembodiments, the total daily dosage for a human subject may be about 900mg/day administered in a single dose. In some embodiments, the totaldaily dosage for a human subject may be about 950 mg/day administered ina single dose. In some embodiments, the total daily dosage for a humansubject may be about 1000 mg/day administered in a single dose.

A single dose can be administered hourly, daily, weekly, or monthly. Forexample, a single dose can be administered once every 1 hour, 2, 3, 4,6, 8, 12, 16 or once every 24 hours. A single dose can also beadministered once every 1 day, 2, 3, 4, 5, 6, or once every 7 days. Asingle dose can also be administered once every 1 week, 2, 3, or onceevery 4 weeks. In certain embodiments, a single dose can be administeredonce every week. A single dose can also be administered once everymonth. In some embodiments, a compound disclosed herein is administeredonce daily in a method disclosed herein. In some embodiments, a compounddisclosed herein is administered twice daily in a method disclosedherein.

The frequency of dosage of the compound of the present disclosure willbe determined by the needs of the individual patient and can be, forexample, once per day or twice, or more times, per day. Administrationof the compound continues for as long as necessary to treat the HBVinfection, HIV infection, cancer, hyper-proliferative disease, or anyother indication described herein. For example, a compound can beadministered to a human being infected with HBV for a period of from 20days to 180 days or, for example, for a period of from 20 days to 90days or, for example, for a period of from 30 days to 60 days.

Administration can be intermittent, with a period of several or moredays during which a patient receives a daily dose of the compound of thepresent disclosure followed by a period of several or more days duringwhich a patient does not receive a daily dose of the compound. Forexample, a patient can receive a dose of the compound every other day,or three times per week. Again by way of example, a patient can receivea dose of the compound each day for a period of from 1 to 14 days,followed by a period of 7 to 21 days during which the patient does notreceive a dose of the compound, followed by a subsequent period (e.g.,from 1 to 14 days) during which the patient again receives a daily doseof the compound. Alternating periods of administration of the compound,followed by non-administration of the compound, can be repeated asclinically required to treat the patient.

The compounds of the present disclosure or the pharmaceuticalcompositions thereof may be administered once, twice, three, or fourtimes daily, using any suitable mode described above. Also,administration or treatment with the compounds may be continued for anumber of days; for example, commonly treatment would continue for atleast 7 days, 14 days, or 28 days, for one cycle of treatment. Treatmentcycles may be alternated with resting periods of about 1 to 28 days,commonly about 7 days or about 14 days, between cycles. The treatmentcycles, in other embodiments, may also be continuous.

VI. Combination Therapy

In some embodiments, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with one, two,three, four or more additional therapeutic agents. In some embodiments,a compound of the present disclosure, or a pharmaceutically acceptablesalt thereof, is combined with two additional therapeutic agents. Insome embodiments, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with threeadditional therapeutic agents. In some embodiments, a compound of thepresent disclosure, or a pharmaceutically acceptable salt thereof, iscombined with four additional therapeutic agents. The one, two, three,four or more additional therapeutic agents can be different therapeuticagents selected from the same class of therapeutic agents, and/or theycan be selected from different classes of therapeutic agents.

In some embodiments, when a compound of the present disclosure iscombined with one or more additional therapeutic agents as describedherein, the components of the composition are administered as asimultaneous or sequential regimen. When administered sequentially, thecombination may be administered in two or more administrations.

In some embodiments, a compound of the present disclosure is combinedwith one or more additional therapeutic agents in a unitary dosage formfor simultaneous administration to a patient, for example as a soliddosage form for oral administration.

In some embodiments, a compound of the present disclosure isco-administered with one or more additional therapeutic agents.

Co-administration includes administration of unit dosages of thecompounds disclosed herein before or after administration of unitdosages of one or more additional therapeutic agents. The compoundsdisclosed herein may be administered within seconds, minutes, or hoursof the administration of one or more additional therapeutic agents. Forexample, in some embodiments, a unit dose of a compound disclosed hereinis administered first, followed within seconds or minutes byadministration of a unit dose of one or more additional therapeuticagents. Alternatively, in other embodiments, a unit dose of one or moreadditional therapeutic agents is administered first, followed byadministration of a unit dose of a compound disclosed herein withinseconds or minutes. In some embodiments, a unit dose of a compounddisclosed herein is administered first, followed, after a period ofhours (e.g., 1-12 hours), by administration of a unit dose of one ormore additional therapeutic agents. In other embodiments, a unit dose ofone or more additional therapeutic agents is administered first,followed, after a period of hours (e.g., 1-12 hours), by administrationof a unit dose of a compound disclosed herein.

In some embodiments a compound of Formula I, I-Z, I-E, II-Z, IIa-Z,IIb-Z, III-Z, or IIIa-Z, is formulated as a tablet, which may optionallycontain one or more other compounds useful for treating the diseasebeing treated. In certain embodiments, the tablet can contain anotheractive ingredient for treating a HBV infection, HIV infection, cancer,or a hyper-proliferative disease. In some embodiments, such tablets aresuitable for once daily dosing.

Also provided herein are methods of treatment in which a compound ofFormula I, I-Z, I-E, II-Z, IIa-Z, IIb-Z, III-Z, or IIIa-Z, orpharmaceutically acceptable salt thereof, is given to a patient incombination with one or more additional therapeutic agents or therapy.In some embodiments, the total daily dosage of a compound of Formula I,I-Z, I-E, II-Z, IIa-Z, IIb-Z, III-Z, or IIIa-Z, or a pharmaceuticallyacceptable salt thereof, may be about 300 mg/day administered in asingle dose for a human subject.

HBV Combination Therapy

In certain embodiments, a method for treating or preventing an HBVinfection in a human having or at risk of having the infection isprovided, comprising administering to the human a therapeuticallyeffective amount of a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, in combination with a therapeutically effectiveamount of one or more (e.g., one, two, three, four, one or two, one tothree, or one to four) additional therapeutic agents. In one embodiment,a method for treating an HBV infection in a human having or at risk ofhaving the infection is provided, comprising administering to the humana therapeutically effective amount of a compound disclosed herein, or apharmaceutically acceptable salt thereof, in combination with atherapeutically effective amount of one or more (e.g., one, two, three,four, one or two, one to three, or one to four) additional therapeuticagents.

In certain embodiments, the present disclosure provides a method fortreating an HBV infection, comprising administering to a patient in needthereof a therapeutically effective amount of a compound disclosedherein or a pharmaceutically acceptable salt thereof, in combinationwith a therapeutically effective amount of one or more (e.g., one, two,three, four, one or two, one to three, or one to four) additionaltherapeutic agents which are suitable for treating an HBV infection.

The compounds described herein may be used or combined with one or moreof a chemotherapeutic agent, an immunomodulator, an immunotherapeuticagent, a therapeutic antibody, a therapeutic vaccine, a bispecificantibody and “antibody-like” therapeutic protein (such as DARTs®,Duobodies®, Bites®, XmAbs®, TandAbs®, Fab derivatives), an antibody-drugconjugate (ADC), gene modifiers or gene editors (such as CRISPR Cas9,zinc finger nucleases, homing endonucleases, synthetic nucleases,TALENs), cell therapies such as CAR-T (chimeric antigen receptorT-cell), and TCR-T (an engineered T cell receptor) agent or anycombination thereof.

In certain embodiments, a compound of Formula I, I-Z, I-E, II-Z, IIa-Z,IIb-Z, III-Z, or IIIa-Z is formulated as a tablet, which may optionallycontain one or more other compounds useful for treating HBV. In certainembodiments, the tablet can contain another active ingredient fortreating HBV, such as 3-dioxygenase (IDO) inhibitors, Apolipoprotein A1modulator, arginase inhibitors, B- and T-lymphocyte attenuatorinhibitors, Bruton's tyrosine kinase (BTK) inhibitors, CCR2 chemokineantagonist, CD137 inhibitors, CD160 inhibitors, CD305 inhibitors, CD4agonist and modulator, compounds targeting HBcAg, compounds targetinghepatitis B core antigen (HBcAg), core protein allosteric modulators,covalently closed circular DNA (cccDNA) inhibitors, cyclophilininhibitors, cytotoxic T-lymphocyte-associated protein 4 (ipi4)inhibitors, DNA polymerase inhibitor, Endonuclease modulator, epigeneticmodifiers, Famesoid X receptor agonist, HBsAg inhibitors, HBsAgsecretion or assembly inhibitors, HBV DNA polymerase inhibitors, HBVreplication inhibitors, HBV RNAse inhibitors, HBV viral entryinhibitors, HBx inhibitors, Hepatitis B large envelope proteinmodulator, Hepatitis B large envelope protein stimulator, Hepatitis Bstructural protein modulator, hepatitis B surface antigen (HBsAg)inhibitors, hepatitis B surface antigen (HBsAg) secretion or assemblyinhibitors, hepatitis B virus E antigen inhibitors, hepatitis B virusreplication inhibitors, Hepatitis virus structural protein inhibitor,HIV-1 reverse transcriptase inhibitor, Hyaluronidase inhibitor, IAPsinhibitors, IL-2 agonist, IL-7 agonist, immunomodulators, indoleamine-2inhibitors, inhibitors of ribonucleotide reductase, Interleukin-2ligand, ipi4 inhibitors, lysine demethylase inhibitors, histonedemethylase inhibitors, KDM1 inhibitors, KDM5 inhibitors, killer celllectin-like receptor subfamily G member 1 inhibitors,lymphocyte-activation gene 3 inhibitors, lymphotoxin beta receptoractivators, modulators of Axl, modulators of B7-H3, modulators of B7-H4,modulators of CD160, modulators of CD161, modulators of CD27, modulatorsof CD47, modulators of CD70, modulators of GITR, modulators of HEVEM,modulators of ICOS, modulators of Mer, modulators of NKG2A, modulatorsof NKG2D, modulators of OX40, modulators of SIRPalpha, modulators ofTIGIT, modulators of Tim-4, modulators of Tyro, Na+-taurocholatecotransporting polypeptide (NTCP) inhibitors, natural killer cellreceptor 2B4 inhibitors, NOD2 gene stimulator, Nucleoprotein inhibitor,nucleoprotein modulators, PD-1 inhibitors, PD-L1 inhibitors,Peptidylprolyl isomerase inhibitor, phosphatidylinositol-3 kinase (PI3K)inhibitors, Retinoic acid-inducible gene 1 stimulator, Reversetranscriptase inhibitor, Ribonuclease inhibitor, RNA DNA polymeraseinhibitor, SLC10A1 gene inhibitor, SMAC mimetics, Src tyrosine kinaseinhibitor, stimulator of interferon gene (STING) agonists, stimulatorsof NOD1, T cell surface glycoprotein CD28 inhibitor, T-cell surfaceglycoprotein CD8 modulator, Thymosin agonist, Thymosin alpha 1 ligand,Tim-3 inhibitors, TLR-3 agonist, TLR-7 agonist, TLR-9 agonist, TLR9 genestimulator, toll-like receptor (TLR) modulators, Viral ribonucleotidereductase inhibitor, and combinations thereof.

HBV Combination Drugs

Examples of combination drugs for the treatment of HBV include TRUVADA®(tenofovir disoproxil fumarate and emtricitabine); ABX-203, lamivudine,and PEG-IFN-alpha; ABX-203 adefovir, and PEG-IFNalpha; and INO-1800(INO-9112 and RG7944).

Other HBV Drugs

Examples of other drugs for the treatment of HBV includealpha-hydroxytropolones, amdoxovir, beta-hydroxycytosine nucleosides,AL-034, CCC-0975, elvucitabine, ezetimibe, cyclosporin A, gentiopicrin(gentiopicroside), JNJ-56136379, nitazoxanide, birinapant, NJK14047,NOV-205 (molixan, BAM-205), oligotide, mivotilate, feron, GST-HG-131,levamisole, Ka Shu Ning, alloferon, WS-007, Y-101 (Ti Fen Tai),rSIFN-co, PEG-IIFNm, KW-3, BP-Inter-014, oleanolic acid, HepB-nRNA,cTP-5 (rTP-5), HSK-II-2, HEISCO-106-1, HEISCO-106, Hepbarna, IBPB-0061A,Hepuyinfen, DasKloster 0014-01, ISA-204, Jiangantai (Ganxikang),MIV-210, OB-AI-004, PF-06, picroside, DasKloster-0039, hepulantai,IMB-2613, TCM-800B, reduced glutathione, RO-6864018, RG-7834, UB-551,and ZH-2N, and the compounds disclosed in US20150210682, (Roche), US2016/0122344 (Roche), WO2015173164, WO2016023877, US2015252057A (Roche),W16128335A (Roche), WO16120186A1 (Roche), US2016237090A (Roche),WO16107833A1 (Roche), WO16107832A (Roche), US2016176899A (Roche),W16102438A (Roche), WO16012470A (Roche), US2016220586A (Roche), andUS2015031687A (Roche).

HBV Vaccines

HBV vaccines include both prophylactic and therapeutic vaccines.Examples of HBV prophylactic vaccines include Vaxelis, Hexaxim,Heplisav, Mosquirix, DTwP-HBV vaccine, Bio-Hep-B, D/T/P/HBV/M(LBVP-0101; LBVW-0101), DTwP-Hepb-Hib-IPV vaccine, Heberpenta L,DTwP-HepB-Hib, V-419, CVI-HBV-001, Tetrabhay, hepatitis B prophylacticvaccine (Advax Super D), Hepatrol-07, GSK-223192A, ENGERIX B®,recombinant hepatitis B vaccine (intramuscular, Kangtai BiologicalProducts), recombinant hepatitis B vaccine (Hansenual polymorpha yeast,intramuscular, Hualan Biological Engineering), recombinant hepatitis Bsurface antigen vaccine, Bimmugen, Euforavac, Eutravac,anrix-DTaP-IPV-Hep B, HBAI-20, Infanrix-DTaP-IPV-Hep B-Hib, PentabioVaksin DTP-HB-Hib, Comvac 4, Twinrix, Euvax-B, Tritanrix HB, InfanrixHep B, Comvax, DTP-Hib-HBV vaccine, DTP-HBV vaccine, Yi Tai, HeberbiovacHB, Trivac HB, GerVax, DTwP-Hep B-Hib vaccine, Bilive, Hepavax-Gene,SUPERVAX, Comvac5, Shanvac-B, Hebsulin, Recombivax HB, Revac B mcf,Revac B+, Fendrix, DTwP-HepB-Hib, DNA-001, Shan5, Shan6, rhHBsAGvaccine, HBI pentavalent vaccine, LBVD, Infanrix HeXa, and DTaP-rHB-Hibvaccine.

Examples of HBV therapeutic vaccines include HBsAG-HBIG complex,ARB-1598, Bio-Hep-B, NASVAC, abi-HB (intravenous), ABX-203, Tetrabhay,GX-110E, GS-4774, peptide vaccine (epsilonPA-44), Hepatrol-07, NASVAC(NASTERAP), IMP-321, BEVAC, Revac B mcf, Revac B+, MGN-1333, KW-2,CVI-HBV-002, AltraHepB, VGX-6200, FP-02, FP-02.2, TG-1050, NU-500,HBVax, im/TriGrid/antigen vaccine, Mega-CD40L-adjuvanted vaccine,HepB-v, RG7944 (INO-1800), recombinant VLP-based therapeutic vaccine(HBV infection, VLP Biotech), AdTG-17909, AdTG-17910 AdTG-18202,ChronVac-B, TG-1050, and Lm HBV.

HBV DNA Polymerase Inhibitors

Examples of HBV DNA polymerase inhibitors include adefovir (HEPSERA®),emtricitabine (EMTRIVA®), tenofovir disoproxil fumarate (VIREAD®),tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofoviralafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovirdipivoxil, tenofovir dipivoxil fumarate, tenofovir octadecyloxyethylester, CMX-157, besifovir, entecavir (BARACLUDE®), entecavir maleate,telbivudine (TYZEKA®), filocilovir, pradefovir, clevudine, ribavirin,lamivudine (EPIVIR-HBV®), phosphazide, famciclovir, fusolin, metacavir,SNC-019754, FMCA, AGX-1009, AR-II-04-26, HIP-1302, tenofovir disoproxilaspartate, tenofovir disoproxil orotate, and HS-10234.

Immunomodulators

Examples of immunomodulators include rintatolimod, imidol hydrochloride,ingaron, dermaVir, plaquenil (hydroxychloroquine), proleukin,hydroxyurea, mycophenolate mofetil (MPA) and its ester derivativemycophenolate mofetil (MMF), JNJ-440, WF-10, AB-452, ribavirin, IL-12,INO-9112, polymer polyethyleneimine (PEI), Gepon, VGV-1, MOR-22,CRV-431, JNJ-0535, TG-1050, ABI-H2158, BMS-936559, GS-9688, RO-7011785,RG-7854, AB-506, RO-6871765, AIC-649, and IR-103.

Toll-Like Receptor (TLR) Modulators

TLR modulators include modulators of TLR1, TLR2, TLR3, TLR4, TLR5, TLR6,TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13. Examples of TLR3modulators include rintatolimod, poly-ICLC, RIBOXXON®, Apoxxim,RIBOXXIM®, IPH-33, MCT-465, MCT-475, and ND-1.1.

Examples of TLR7 modulators include GS-9620 (vesatolimod), GSK-2245035,imiquimod, resiquimod, DSR-6434, DSP-3025, IMO-4200, MCT-465, MEDI-9197,3M-051, SB-9922, 3M-052, Limtop, D, telratolimod, SP-0509, TMX-30X,TMX-202, RG-7863, RG-7795, LHC-165, RG-7854, and the compounds disclosedin US20100143301 (Gilead Sciences), US20110098248 (Gilead Sciences), andUS20090047249 (Gilead Sciences).

Examples of TLR8 modulators include motolimod, resiquimod, 3M-051,3M-052, MCT-465, IMO-4200, VTX-763, VTX-1463, GS-9688 and the compoundsdisclosed in US20140045849 (Janssen), US20140073642 (Janssen),WO2014/056953 (Janssen), WO2014/076221 (Janssen), WO2014/128189(Janssen), US20140350031 (Janssen), WO2014/023813 (Janssen),US20080234251 (Array Biopharma), US20080306050 (Array Biopharma),US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma),US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma),US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma),US20140088085 (Ventirx Pharma), US20140275167 (Novira Therapeutics),US20130251673 (Novira Therapeutics), U.S. Pat. No. 9,670,205US20160289229, U.S. patent application Ser. No. 15/692,161 and U.S.patent application Ser. No. 15/692,093.

Examples of TLR9 modulators include BB-001, BB-006, CYT-003, IMO-2055,IMO-2125, IMO-3100, IMO-8400, IR-103, IMO-9200, agatolimod, DIMS-9054,DV-1079, DV-1179, AZD-1419, leftolimod (MGN-1703), litenimod, andCYT-003-QbG10.

Examples of TLR7, TLR8 and TLR9 modulators include the compoundsdisclosed in WO2017047769 (Teika Seiyaku), WO2015014815 (Janssen),WO2018045150 (Gilead Sciences Inc), WO2018045144 (Gilead Sciences Inc),WO2015162075 (Roche), WO2017034986 (University of Kansas), WO2018095426(Jiangsu Hengrui Medicine Co Ltd), WO2016091698 (Roche), WO2016075661(GaxoSmithKline Biologicals), WO2016180743 (Roche), WO2018089695(Dynavax Technologies), WO2016055553 (Roche), WO2015168279 (Novartis),WO2016107536 (Medshine Discovery), WO2018086593 (Livo (Shanghai)Pharmaceutical), WO2017106607 (Merck), WO2017061532 (Sumitomo DainipponPharma), WO2016023511 (Chia Tai Tianqing Pharmaceutical), WO2017076346(Chia Tai Tianqing Pharmaceutical), WO2017046112 (Roche), WO2018078149(Roche), WO2017040233 (3M Co), WO2016141092 (Gilead Sciences),WO2018049089 (Bristol Myers Squibb), WO2015057655 (Eisai Co Ltd),WO2017001307 (Roche), WO2018005586 (Bristol Myers Squibb), WO201704023(3M Co), WO2017163264 (Council of Scientific and Industrial Research(India)), WO2018046460 (GaxoSmithKline Biologicals), WO2018047081(Novartis), WO2016142250 (Roche), WO2015168269 (Novartis), WO201804163(Roche), WO2018038877 (3M Co), WO2015057659 (Eisai Co Ltd), WO2017202704(Roche), WO2018026620 (Bristol Myers Squibb), WO2016029077 (JanusBiotherapeutics), WO201803143 (Merck), WO2016096778 (Roche),WO2017190669 (Shanghai De Novo Pharmatech), U.S. Ser. No. 09/884,866(University of Minnesota), WO2017219931 (Sichuan KelunBiotechBiopharmaceutical), WO2018002319 (Janssen Sciences), WO2017216054(Roche), WO2017202703 (Roche), WO2017184735 (IFM Therapeutics),WO2017184746 (IFM Therapeutics), WO2015088045 (Takeda Pharmaceutical),WO2017038909 (Takeda Pharmaceutical), WO2015095780 (University ofKansas), WO2015023958 (University of Kansas)

Interferon Alpha Receptor Ligands

Examples of interferon alpha receptor ligands include interferonalpha-2b (INTRON A®), pegylated interferon alpha-2a (PEGASYS®),PEGylated interferon alpha-1b, interferon alpha 1b (HAPGEN®), Veldona,Infradure, Roferon-A, YPEG-interferon alfa-2a (YPEG-rhIFNalpha-2a),P-1101, Algeron, Alfarona, Ingaron (interferon gamma), rSIFN-co(recombinant super compound interferon), Ypeginterferon alfa-2b(YPEG-rhIFNalpha-2b), MOR-22, peginterferon alfa-2b (PEG-INTRON®),Bioferon, Novaferon, Inmutag (Inferon), MULTIFERON®, interferon alfa-n1(HUMOFERON®), interferon beta-1a (AVONEX®), Shaferon, interferon alfa-2b(Axxo), Alfaferone, interferon alfa-2b (BioGeneric Pharma),interferon-alpha 2 (CJ), Laferonum, VIPEG, BLAUFERON-A, BLAUFERON-B,Intermax Alpha, Realdiron, Lanstion, Pegaferon, PDferon-B, interferonalfa-2b (IFN, Laboratorios Bioprofarma), alfainterferona 2b, Kalferon,Pegnano, Feronsure, PegiHep, interferon alfa 2b (Zydus-Cadila),interferon alfa 2a, Optipeg A, Realfa 2B, Reliferon, interferon alfa-2b(Amega), interferon alfa-2b (Virchow), ropeginterferon alfa-2b, rHSA-IFNalpha-2a (recombinant human serum albumin intereferon alpha 2a fusionprotein), rHSA-IFN alpha 2b, recombinant human interferon alpha-(1b, 2a,2b), peginterferon alfa-2b (Amega), peginterferon alfa-2a, Reaferon-EC,Proquiferon, Uniferon, Urifron, interferon alfa-2b (Changchun Instituteof Biological Products), Anterferon, Shanferon, Layfferon, Shang ShengLei Tai, INTEFEN, SINOGEN, Fukangtai, Pegstat, rHSA-IFN alpha-2b,SFR-9216, and Interapo (Interapa).

Hyaluronidase Inhibitors

Examples of hyaluronidase inhibitors include astodrimer.

Hepatitis B Surface Antigen (HBsAg) Inhibitors

Examples of HBsAg inhibitors include HBF-0259, PBHBV-001, PBHBV-2-15,PBHBV-2-1, REP-9AC, REP-9C, REP-9, REP-2139, REP-2139-Ca, REP-2165,REP-2055, REP-2163, REP-2165, REP-2053, REP-2031 and REP-006, andREP-9AC′.

Examples of HBsAg secretion inhibitors include BM601.

Cytotoxic T-Lymphocyte-Associated Protein 4 (Ipi4) Inhibitors

Examples of Cytotoxic T-lymphocyte-associated protein 4 (ipi4)inhibitors include AGEN-2041, AGEN-1884, ipilumimab, belatacept,PSI-001, PRS-010, Probody mAbs, tremelimumab, and JHL-1155.

Cyclophilin Inhibitors

Examples of cyclophilin inhibitors include CPI-431-32, EDP-494, OCB-030,SCY-635, NVP-015, NVP-018, NVP-019, STG-175, and the compounds disclosedin U.S. Pat. No. 8,513,184 (Gilead Sciences), US20140030221 (GileadSciences), US20130344030 (Gilead Sciences), and US20130344029 (GileadSciences).

HBV Viral Entry Inhibitors

Examples of HBV viral entry inhibitors include Myrcludex B.

Antisense Oligonucleotide Targeting Viral mRNA

Examples of antisense oligonucleotide targeting viral mRNA includeISIS-HBVRx, IONIS-HBVRx, IONIS-GSK6-LRx, GSK-3389404, RG-6004.

Short Interfering RNAs (siRNA) and ddRNAi

Examples of siRNA include TKM-HBV (TKM-HepB), ALN—HBV, SR-008,HepB-nRNA, and ARC-520, ARC-521, ARB-1740, ARB-1467.

Examples of DNA-directed RNA interference (ddRNAi) include BB-HB-331.

Endonuclease Modulators

Examples of endonuclease modulators include PGN-514.

Ribonucelotide Reductase Inhibitors

Examples of inhibitors of ribonucleotide reductase include Trimidox.

HBV EAntigen Inhibitors

Examples of HBV E antigen inhibitors include wogonin.

Covalently Closed Circular DNA (cccDNA) Inhibitors

Examples of cccDNA inhibitors include BSBI-25, and CHR-101.

Farnesoid X Receptor Agonist

Examples of famesoid x receptor agonist such as EYP-001, GS-9674,EDP-305, MET-409, Tropifexor, AKN-083, RDX-023, BWD-100, LMB-763, INV-3,NTX-023-1, EP-024297 and GS-8670

HBV Antibodies

Examples of HBV antibodies targeting the surface antigens of thehepatitis B virus include GC-1102, XTL-17, XTL-19, KN-003, IV HepabulinSN, and fully human monoclonal antibody therapy (hepatitis B virusinfection, Humabs BioMed).

Examples of HBV antibodies, including monoclonal antibodies andpolyclonal antibodies, include Zutectra, Shang Sheng Gan Di, Uman Big(Hepatitis B Hyperimmune), Omri-Hep-B, Nabi-HB, Hepatect CP, HepaGam B,igantibe, Niuliva, CT-P24, hepatitis B immunoglobulin (intravenous, pH4,HBV infection, Shanghai RAAS Blood Products), and Fovepta (BT-088).

Fully human monoclonal antibodies include HBC-34.

CCR2 Chemokine Antagonists

Examples of CCR2 chemokine antagonists include propagermanium.

Thymosin Agonists

Examples of thymosin agonists include Thymalfasin, recombinant thymosinalpha 1 (GeneScience)

Cytokines

Examples of cytokines include recombinant IL-7, CYT-107, interleukin-2(IL-2, Immunex), recombinant human interleukin-2 (Shenzhen Neptunus),IL-15, IL-21, IL-24, and celmoleukin.

Nucleoprotein Modulators

Nucleoprotein modulators may be either HBV core or capsid proteininhibitors. Examples of nucleoprotein modulators include GS-4882,AB-423, AT-130, GLS4, NVR-1221, NVR-3778, AL-3778, BAY 41-4109,morphothiadine mesilate, ARB-168786, ARB-880, JNJ-379, RG-7907,HEC-72702, AB-506, ABI-H0731, JNJ-440, ABI-H2158 and DVR-23.

Examples of capsid inhibitors include the compounds disclosed inUS20140275167 (Novira Therapeutics), US20130251673 (NoviraTherapeutics), US20140343032 (Roche), WO2014037480 (Roche),US20130267517 (Roche), WO2014131847 (Janssen), WO2014033176 (Janssen),WO2014033170 (Janssen), WO2014033167 (Janssen), WO2015/059212 (Janssen),WO2015118057 (Janssen), WO2015011281 (Janssen), WO2014184365 (Janssen),WO2014184350 (Janssen), WO2014161888 (Janssen), WO2013096744 (Novira),US20150225355 (Novira), US20140178337 (Novira), US20150315159 (Novira),US20150197533 (Novira), US20150274652 (Novira), US20150259324, (Novira),US20150132258 (Novira), U.S. Pat. No. 9,181,288 (Novira), WO2014184350(Janssen), WO2013144129 (Roche), WO2017198744 (Roche), US 20170334882(Novira), US 20170334898 (Roche), WO2017202798 (Roche), WO2017214395(Enanta), WO2018001944 (Roche), WO2018001952 (Roche), W2018005881(Novira), W2018005883 (Novira), WO2018011100 (Roche), WO2018011160(Roche), WO2018011162 (Roche), WO2018011163 (Roche), WO2018036941(Roche), W2018043747 (Kyoto Univ), US20180065929 (Janssen), WO2016168619(Indiana University), WO2016195982 (The Penn State Foundation),WO2017001655 (Janssen), WO2017048950 (Assembly Biosciences),WO2017048954 (Assembly Biosciences), WO2017048962 (AssemblyBiosciences), US20170121328 (Novira), US20170121329 (Novira).

Examples of transcript inhibitors include the compounds disclosed inWO2017013046 (Roche), WO2017016960 (Roche), WO2017017042 (Roche),WO2017017043 (Roche), WO2017061466 (Toyoma chemicals), WO2016177655(Roche), WO2016161268 (Enanta). WO2017001853 (Redex Pharma),WO2017211791 (Roche), WO2017216685 (Novartis), WO2017216686 (Novartis),WO2018019297 (Ginkgo Pharma), WO2018022282 (Newave Pharma),US20180030053 (Novartis), WO2018045911 (Zhejiang Pharma).

Retinoic Acid-Inducible Gene 1 Stimulators

Examples of stimulators of retinoic acid-inducible gene 1 includeSB-9200, SB-40, SB-44, ORI-7246, ORI-9350, ORI-7537, ORI-9020, ORI-9198,and ORI-7170, RGT-100.

NOD2 Stimulators

Examples of stimulators of NOD2 include SB-9200.

Phosphatidylinositol 3-kinase (PI3K) Inhibitors

Examples of PI3K inhibitors include idelalisib, ACP-319, AZD-8186,AZD-8835, buparlisib, CDZ-173, CLR-457, pictilisib, neratinib,rigosertib, rigosertib sodium, EN-3342, TGR-1202, alpelisib, duvelisib,IPI-549, UCB-5857, taselisib, XL-765, gedatolisib, ME-401, VS-5584,copanlisib, CAI orotate, perifosine, RG-7666, GSK-2636771, DS-7423,panulisib, GSK-2269557, GSK-2126458, CUDC-907, PQR-309, INCB-40093,pilaralisib, BAY-1082439, puquitinib mesylate, SAR-245409, AMG-319,RP-6530, ZSTK-474, MLN-1117, SF-1126, RV-1729, sonolisib, LY-3023414,SAR-260301, TAK-117, HMPL-689, tenalisib, voxtalisib, and CLR-1401.

Indoleamine-2,3-dioxygenase (IDO) Pathway Inhibitors

Examples of IDO inhibitors include epacadostat (INCB24360), resminostat(4SC-201), indoximod, F-001287, SN-35837, NLG-919, GDC-0919, GBV-1028,GBV-1012, NKTR-218, and the compounds disclosed in US20100015178(Incyte), US2016137652 (Flexus Biosciences, Inc.), WO2014073738 (FlexusBiosciences, Inc.), and W2015188085 (Flexus Biosciences, Inc.).

PD-1 Inhibitors

Examples of PD-1 inhibitors include cemiplimab, nivolumab,pembrolizumab, pidilizumab, BGB-108, STI-A1014, SHR-1210, PDR-001,PF-06801591, IBI-308, GB-226, STI-1110, JNJ-63723283, CA-170,durvalumab, atezolizumab and mDX-400, JS-001, Camrelizumab, Sintilimab,Sintilimab, tislelizumab, BCD-100, BGB-A333 JNJ-63723283, GLS-010(WBP-3055), CX-072, AGEN-2034, GNS-1480 (Epidermal growth factorreceptor antagonist; Programmed cell death ligand 1 inhibitor), CS-1001,M-7824 (PD-L1/TGF-β bifunctional fusion protein), Genolimzumab,BMS-936559.

PD-L1 Inhibitors

Examples of PD-L1 inhibitors include atezolizumab, avelumab, AMP-224,MEDI-0680, RG-7446, GX-P2, durvalumab, KY-1003, KD-033, MSB-0010718C,TSR-042, ALN-PDL, STI-A1014, GS-4224, CX-072, and BMS-936559.

Examples of PD-1 inhibitors include the compounds disclosed inWO2017112730 (Incyte Corp), WO2017087777 (Incyte Corp), WO2017017624,WO2014151634 (Bristol Myers Squibb Co), WO201317322 (Bristol MyersSquibb Co), WO2018119286 (Incyte Corp), WO2018119266 (Incyte Corp),WO2018119263 (Incyte Corp), WO2018119236 (Incyte Corp), WO2018119221(Incyte Corp), WO2018118848 (Bristol Myers Squibb Co), WO20161266460(Bristol Myers Squibb Co), WO2017087678 (Bristol Myers Squibb Co),WO2016149351 (Bristol Myers Squibb Co), WO2015033299 (Aurigene DiscoveryTechnologies Ltd), WO2015179615 (Eisai Co Ltd; Eisai ResearchInstitute), WO2017066227 (Bristol Myers Squibb Co), WO2016142886(Aurigene Discovery Technologies Ltd), WO2016142852 (Aurigene DiscoveryTechnologies Ltd), WO2016142835 (Aurigene Discovery Technologies Ltd;Individual), WO2016142833 (Aurigene Discovery Technologies Ltd),WO2018085750 (Bristol Myers Squibb Co), WO2015033303 (Aurigene DiscoveryTechnologies Ltd), WO2017205464 (Incyte Corp), WO2016019232 (3M Co;Individual; Texas A&M University System), WO2015160641 (Bristol MyersSquibb Co), WO2017079669 (Incyte Corp), WO2015033301 (Aurigene DiscoveryTechnologies Ltd), WO2015034820 (Bristol Myers Squibb Co), WO2018073754(Aurigene Discovery Technologies Ltd), WO2016077518 (Bristol MyersSquibb Co), WO2016057624 (Bristol Myers Squibb Co), WO2018044783 (IncyteCorp), WO2016100608 (Bristol Myers Squibb Co), WO2016100285 (BristolMyers Squibb Co), WO2016039749 (Bristol Myers Squibb Co), WO2015019284(Cambridge Enterprise Ltd), WO2016142894 (Aurigene DiscoveryTechnologies Ltd), WO2015134605 (Bristol Myers Squibb Co), WO2018051255(Aurigene Discovery Technologies Ltd), WO2018051254 (Aurigene DiscoveryTechnologies Ltd), WO2017222976 (Incyte Corp), WO2017070089 (IncyteCorp), WO2018044963 (Bristol Myers Squibb Co), WO2013144704 (AurigeneDiscovery Technologies Ltd), WO2018013789 (Incyte Corp), WO2017176608(Bristol Myers Squibb Co), WO2018009505 (Bristol Myers Squibb Co),WO2011161699 (Aurigene Discovery Technologies Ltd), WO2015119944 (IncyteCorp; Merck Sharp & Dohme Corp), WO2017192961 (Incyte Corp),WO2017106634 (Incyte Corp), WO2013132317 (Aurigene DiscoveryTechnologies Ltd), WO2012168944 (Aurigene Discovery Technologies Ltd),WO2015036927 (Aurigene Discovery Technologies Ltd), WO2015044900(Aurigene Discovery Technologies Ltd), WO2018026971 (ArisingInternational).

Other examples of PD-1 and/or PDL-1 inhibitors include the compoundsdisclosed in U.S. Provisional Serial Nos. 62/630,187, 62/640,534,62/736,116, and 62/747,029.

Recombinant Thymosin Alpha-1

Examples of recombinant thymosin alpha-1 include NL-004 and PEGylatedthymosin alpha-1.

Bruton's Tyrosine Kinase (BTK) Inhibitors

Examples of BTK inhibitors include ABBV-105, acalabrutinib (ACP-196),ARQ-531, BMS-986142, dasatinib, ibrutinib, GDC-0853, PRN-1008, SNS-062,ONO-4059, BGB-3111, ML-319, MSC-2364447, RDX-022, X-022, AC-058,RG-7845, spebrutinib, TAS-5315, TP-0158, TP-4207, HM-71224, KBP-7536,M-2951, TAK-020, AC-0025, and the compounds disclosed in US20140330015(Ono Pharmaceutical), US20130079327 (Ono Pharmaceutical), andUS20130217880 (Ono Pharmaceutical).

KDM Inhibitors

Examples of KDM5 inhibitors include the compounds disclosed inWO2016057924 (Genentech/Constellation Pharmaceuticals), US20140275092(Genentech/Constellation Pharmaceuticals), US20140371195(Epitherapeutics) and US20140371214 (Epitherapeutics), US20160102096(Epitherapeutics), US20140194469 (Quanticel), US20140171432,US20140213591 (Quanticel), US20160039808 (Quanticel), US20140275084(Quanticel), WO2014164708 (Quanticel).

Examples of KDM1 inhibitors include the compounds disclosed in U.S. Pat.No. 9,186,337B2 (Oryzon Genomics), GSK-2879552, and RG-6016.

STING Agonists

Examples of STING agonists include SB-11285, AdVCA0848, STINGVAX, andthe compounds disclosed in WO 2018065360 (“Biolog Life Science InstituteForschungslabor und Biochemica-Vertrieb GmbH, Germany), WO 2018009466(Aduro Biotech), WO 2017186711 (InvivoGen), WO 2017161349 (ImmuneSensor), WO 2017106740 (Aduro Biotech), US 20170158724 (GlaxoSmithkiline), WO 2017075477 (Aduro Biotech), US 20170044206 (Merck), WO2014179760 (University of California), WO2018098203 (Janssen),WO2018118665 (Merck), WO2018118664 (Merck), WO2018100558 (Takeda),WO2018067423 (Merck), WO2018060323 (Boehringer).

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI)

Examples of NNRTI include the compounds disclosed in WO2018118826(Merck), WO2018080903 (Merck), WO2018119013 (Merck), WO2017100108(Idenix), WO2017027434 (Merck), WO2017007701 (Merck), WO2008005555(Gilead).

HBV Replication Inhibitors

Examples of hepatitis B virus replication inhibitors includeisothiafludine, IQP-HBV, RM-5038, and Xingantie.

Arginase Inhibitors

Examples of Arginase inhibitors include CB-1158, C-201, and resminostat.

Gene Therapy and Cell Therapy

Gene therapy and cell therapy includes the genetic modification tosilence a gene; genetic approaches to directly kill the infected cells;the infusion of immune cells designed to replace most of the patient'sown immune system to enhance the immune response to infected cells, oractivate the patient's own immune system to kill infected cells, or findand kill the infected cells; and genetic approaches to modify cellularactivity to further alter endogenous immune responsiveness against theinfection.

Gene Editors

Examples of genome editing systems include a CRISPR/Cas9 system, a zincfinger nuclease system, a TALEN system, a homing endonucleases system,and a meganuclease system; e.g., cccDNA elimination via targetedcleavage, and altering one or more of the hepatitis B virus (HBV) viralgenes. Altering (e.g., knocking out and/or knocking down) the PreC, C, XPreSI, PreS2, S, P or SP gene refers to (1) reducing or eliminatingPreC, C, X PreSI, PreS2, S, P or SP gene expression, (2) interferingwith Precore, Core, X protein, Long surface protein, middle surfaceprotein, S protein (also known as HBs antigen and HBsAg), polymeraseprotein, and/or Hepatitis B spliced protein function (HBe, HBc, HBx,PreS1, PreS2, S, Pol, and/or HBSP or (3) reducing or eliminating theintracellular, serum and/or intraparenchymal levels of HBe, HBc, HBx,LHBs, MHBs, SHBs, Pol, and/or HBSP proteins. Knockdown of one or more ofthe PreC, C, X PreS1, PreS2, S, P and/or SP gene(s) is performed bytargeting the gene(s) within HBV cccDNA and/or integrated HBV DNA.

CAR-T Cell Therapy

CAR T cell therapy includes a population of immune effector cellsengineered to express a chimeric antigen receptor (CAR), wherein the CARcomprises an HBV antigen-binding domain. The immune effector cell is a Tcell or an NK cell. In some embodiments, the T cell is a CD4+ T cell, aCD8+ T cell, or a combination thereof. Cells can be autologous orallogeneic.

TCR-T Cell Therapy

TCR T cell therapy includes T cells expressing HBV-specific T cellreceptors. TCR-T cells are engineered to target HBV derived peptidespresented on the surface of virus-infected cells. In some embodiments,the T-cells express HBV surface antigen (HBsAg)-specific TCR. Examplesof TCR-T therapy directed to treatment of HBV include LTCR-H2-1.

In another specific embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with an HBV DNApolymerase inhibitor, one or two additional therapeutic agents selectedfrom the group consisting of immunomodulators, TLR modulators, HBsAginhibitors, HBsAg secretion or assembly inhibitors, HBV therapeuticvaccines, HBV antibodies including HBV antibodies targeting the surfaceantigens of the hepatitis B virus and bispecific antibodies and“antibody-like” therapeutic proteins (such as DARTs®, DUOBODIES®,BITES®, XmAbs®, TandAbs®, Fab derivatives, or TCR-like antibodies),cyclophilin inhibitors, stimulators of retinoic acid-inducible gene 1,stimulators of RIG-I like receptors, PD-1 inhibitors, PD-L1 inhibitors,Arginase inhibitors, PI3K inhibitors, IDO inhibitors, and stimulators ofNOD2, and one or two additional therapeutic agents selected from thegroup consisting of HBV viral entry inhibitors, NTCP inhibitors, HBxinhibitors, cccDNA inhibitors, HBV antibodies targeting the surfaceantigens of the hepatitis B virus, siRNA, miRNA gene therapy agents,sshRNAs, KDM5 inhibitors, and nucleoprotein modulators (HBV core orcapsid protein modulators).

In another specific embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with an HBV DNApolymerase inhibitor and at least a second additional therapeutic agentselected from the group consisting of: immunomodulators, TLR modulators,HBsAg inhibitors, HBV therapeutic vaccines, HBV antibodies including HBVantibodies targeting the surface antigens of the hepatitis B virus andbispecific antibodies and “antibody-like” therapeutic proteins (such asDARTs®, DUOBODIES®, BITES®, XmAbs®, TandAbs©, Fab derivatives, orTCR-like antibodies), cyclophilin inhibitors, stimulators of retinoicacid-inducible gene 1, stimulators of RIG-I like receptors, PD-1inhibitors, PD-L1 inhibitors, Arginase inhibitors, PI3K inhibitors, IDOinhibitors, and stimulators of NOD2.

In another specific embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with an HBV DNApolymerase inhibitor and at least a second additional therapeutic agentselected from the group consisting of: HBV viral entry inhibitors, NTCPinhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targetingthe surface antigens of the hepatitis B virus, siRNA, miRNA gene therapyagents, sshRNAs, KDM5 inhibitors, and nucleoprotein modulators (HBV coreor capsid protein inhibitors).

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with compoundssuch as those disclosed in U.S. Publication No. 2010/0143301 (GileadSciences), U.S. Publication No. 2011/0098248 (Gilead Sciences), U.S.Publication No. 2009/0047249 (Gilead Sciences), U.S. Pat. No. 8,722,054(Gilead Sciences), U.S. Publication No. 2014/0045849 (Janssen), U.S.Publication No. 2014/0073642 (Janssen), WO2014/056953 (Janssen),WO2014/076221 (Janssen), WO2014/128189 (Janssen), U.S. Publication No.2014/0350031 (Janssen), WO2014/023813 (Janssen), U.S. Publication No.2008/0234251 (Array Biopharma), U.S. Publication No. 2008/0306050 (ArrayBiopharma), U.S. Publication No. 2010/0029585 (Ventirx Pharma), U.S.Publication No. 2011/0092485 (Ventirx Pharma), US2011/0118235 (VentirxPharma), U.S. Publication No. 2012/0082658 (Ventirx Pharma), U.S.Publication No. 2012/0219615 (Ventirx Pharma), U.S. Publication No.2014/0066432 (Ventirx Pharma), U.S. Publication No. 2014/0088085(Ventirx Pharma), U.S. Publication No. 2014/0275167 (NoviraTherapeutics), U.S. Publication No. 2013/0251673 (Novira Therapeutics),U.S. Pat. No. 8,513,184 (Gilead Sciences), U.S. Publication No.2014/0030221 (Gilead Sciences), U.S. Publication No. 2013/0344030(Gilead Sciences), U.S. Publication No. 2013/0344029 (Gilead Sciences),US20140275167 (Novira Therapeutics), US20130251673 (NoviraTherapeutics), U.S. Publication No. 2014/0343032 (Roche), WO2014037480(Roche), U.S. Publication No. 2013/0267517 (Roche), WO2014131847(Janssen), WO2014033176 (Janssen), WO2014033170 (Janssen), WO2014033167(Janssen), WO2015/059212 (Janssen), WO2015118057 (Janssen), WO2015011281(Janssen), WO2014184365 (Janssen), WO2014184350 (Janssen), WO2014161888(Janssen), WO2013096744 (Novira), US20150225355 (Novira), US20140178337(Novira), US20150315159 (Novira), US20150197533 (Novira), US20150274652(Novira), US20150259324, (Novira), US20150132258 (Novira), U.S. Pat. No.9,181,288 (Novira), WO2014184350 (Janssen), WO2013144129 (Roche),US20100015178 (Incyte), US2016137652 (Flexus Biosciences, Inc.),WO2014073738 (Flexus Biosciences, Inc.), WO2015188085 (FlexusBiosciences, Inc.), U.S. Publication No. 2014/0330015 (OnoPharmaceutical), U.S. Publication No. 2013/0079327 (Ono Pharmaceutical),U.S. Publication No. 2013/0217880 (Ono pharmaceutical), WO2016057924(Genentech/Constellation Pharmaceuticals), US20140275092(Genentech/Constellation Pharmaceuticals), US20140371195(Epitherapeutics) and US20140371214 (Epitherapeutics), US20160102096(Epitherapeutics), US20140194469 (Quanticel), US20140171432,US20140213591 (Quanticel), US20160039808 (Quanticel), US20140275084(Quanticel), WO2014164708 (Quanticel), U.S. Pat. No. 9,186,337B2 (OryzonGenomics), and other drugs for treating HBV, and combinations thereof.

HIV Combination Therapy

In certain embodiments, a method for treating or preventing an HIVinfection in a human or animal having or at risk of having the infectionis provided, comprising administering to the human or animal atherapeutically effective amount of a compound disclosed herein, or apharmaceutically acceptable salt thereof, in combination with atherapeutically effective amount of one or more (e.g., one, two, three,one or two, or one to three) additional therapeutic agents. In oneembodiment, a method for treating an HIV infection in a human or animalhaving or at risk of having the infection is provided, comprisingadministering to the human or animal a therapeutically effective amountof a compound disclosed herein, or a pharmaceutically acceptable saltthereof, in combination with a therapeutically effective amount of oneor more (e.g., one, two, three, one or two, or one to three) additionaltherapeutic agents.

In one embodiment, pharmaceutical compositions comprising a compounddisclosed herein, or a pharmaceutically acceptable salt thereof, incombination with one or more (e.g., one, two, three, one or two, or oneto three) additional therapeutic agents, and a pharmaceuticallyacceptable carrier, diluent, or excipient are provided.

In certain embodiments, the present disclosure provides a method fortreating an HIV infection, comprising administering to a patient in needthereof a therapeutically effective amount of a compound disclosedherein, or a pharmaceutically acceptable salt thereof, in combinationwith a therapeutically effective amount of one or more additionaltherapeutic agents which are suitable for treating an HIV infection.

In certain embodiments, the compounds disclosed herein are formulated asa tablet, which may optionally contain one or more other compoundsuseful for treating HIV. In certain embodiments, the tablet can containanother active ingredient for treating HIV, such as HIV proteaseinhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reversetranscriptase, HIV nucleoside or nucleotide inhibitors of reversetranscriptase, HIV integrase inhibitors, HIV non-catalytic site (orallosteric) integrase inhibitors, pharmacokinetic enhancers, or anycombinations thereof.

In certain embodiments, such tablets are suitable for once daily dosing.

In some embodiments, the additional therapeutic agent may be an anti-HIVagent. In some embodiments, the additional therapeutic agent is selectedfrom the group consisting of HIV combination drugs, HIV proteaseinhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reversetranscriptase, HIV nucleoside or nucleotide inhibitors of reversetranscriptase, HIV integrase inhibitors, HIV non-catalytic site (orallosteric) integrase inhibitors, HIV entry inhibitors, HIV maturationinhibitors, immunomodulators, immunotherapeutic agents, antibody-drugconjugates, gene modifiers, gene editors (such as CRISPR/Cas9, zincfinger nucleases, homing nucleases, synthetic nucleases, TALENs), celltherapies (such as chimeric antigen receptor T-cell, CAR-T, andengineered T cell receptors, TCR-T), latency reversing agents, compoundsthat target the HIV capsid (including capsid inhibitors), immune-basedtherapies, phosphatidylinositol 3-kinase (PI3K) inhibitors,alpha-4/beta-7 antagonists, HIV antibodies, bispecific antibodies and“antibody-like” therapeutic proteins, HIV p17 matrix protein inhibitors,IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators,protein disulfide isomerase inhibitors, complement C₅a receptorantagonists, DNA methyltransferase inhibitor, HIV vif gene modulators,Vif dimerization antagonists, HIV-1 viral infectivity factor inhibitors,TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinasemodulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicinginhibitors, Rev protein inhibitors, integrin antagonists, nucleoproteininhibitors, splicing factor modulators, COMM domain containing protein 1modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9inhibitors, dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAGprotein inhibitors, HIV POL protein inhibitors, Complement Factor Hmodulators, ubiquitin ligase inhibitors, deoxycytidine kinaseinhibitors, cyclin dependent kinase inhibitors, proprotein convertasePC9 stimulators, ATP dependent RNA helicase DDX3X inhibitors, reversetranscriptase priming complex inhibitors, G6PD and NADH-oxidaseinhibitors, pharmacokinetic enhancers, HIV gene therapy, HIV vaccines,and other HIV therapeutic agents, or any combinations thereof.

In some embodiments, the additional therapeutic agent is selected fromthe group consisting of combination drugs for HIV, other drugs fortreating HIV, HIV protease inhibitors, HIV reverse transcriptaseinhibitors, HIV integrase inhibitors, HIV non-catalytic site (orallosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIVmaturation inhibitors, latency reversing agents, capsid inhibitors,immune-based therapies, PI3K inhibitors, HIV antibodies, and bispecificantibodies, and “antibody-like” therapeutic proteins, or anycombinations thereof.

HIV Combination Drugs

Examples of combination drugs include ATRIPLA® (efavirenz, tenofovirdisoproxil fumarate, and emtricitabine); BIKTARVY® (bictegravir,emtricitabine, and tenofovir alafenamide); COMPLERA® (EVIPLERA®;rilpivirine, tenofovir disoproxil fumarate, and emtricitabine);STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, andemtricitabine); TRUVADA® (tenofovir disoproxil fumarate andemtricitabine; TDF+FTC); DESCOVY® (tenofovir alafenamide andemtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, andrilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine,cobicistat, and elvitegravir); SYMTUZA® (darunavir, tenofoviralafenamide hemifumarate, emtricitabine, and cobicistat); SYMFI™(efavirenz, lamivudine, and tenofovir disoproxil fumarate); CIMDU™(lamivudine and tenofovir disoproxil fumarate); tenofovir andlamivudine; tenofovir alafenamide and emtricitabine; tenofoviralafenamide hemifumarate and emtricitabine; tenofovir alafenamidehemifumarate, emtricitabine, and rilpivirine; tenofovir alafenamidehemifumarate, emtricitabine, cobicistat, and elvitegravir; COMBIVIR®(zidovudine and lamivudine; AZT+3TC); EPZICOM® (LIVEXA®; abacavirsulfate and lamivudine; ABC+3TC); KALETRA® (ALUVIA®; lopinavir andritonavir); TRIUMEQ® (dolutegravir, abacavir, and lamivudine); TRIZIVIR®(abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC); atazanavirand cobicistat; atazanavir sulfate and cobicistat; atazanavir sulfateand ritonavir; darunavir and cobicistat; dolutegravir and rilpivirine;dolutegravir and rilpivirine hydrochloride; dolutegravir, abacavirsulfate, and lamivudine; lamivudine, nevirapine, and zidovudine;raltegravir and lamivudine; doravirine, lamivudine, and tenofovirdisoproxil fumarate; doravirine, lamivudine, and tenofovir disoproxil;dapivirine+levonorgestrel, dolutegravir+lamivudine,dolutegravir+emtricitabine+tenofovir alafenamide,elsulfavirine+emtricitabine+tenofovir disoproxil,lamivudine+abacavir+zidovudine, lamivudine+abacavir,lamivudine+tenofovir disoproxil fumarate,lamivudine+zidovudine+nevirapine, lopinavir+ritonavir,lopinavir+ritonavir+abacavir+lamivudine,lopinavir+ritonavir+zidovudine+lamivudine, tenofovir+lamivudine, andtenofovir disoproxil fumarate+emtricitabine+rilpivirine hydrochloride,lopinavir, ritonavir, zidovudine and lamivudine; Vacc-4× and romidepsin;and APH-0812, or any combinations thereof.

HIV Protease Inhibitors

Examples of HIV protease inhibitors include amprenavir, atazanavir,brecanavir, darunavir, fosamprenavir, fosamprenavir calcium, indinavir,indinavir sulfate, lopinavir, nelfinavir, nelfinavir mesylate,ritonavir, saquinavir, saquinavir mesylate, tipranavir, DG-17, TMB-657(PPL-100), T-169, BL-008, MK-8122, TMB-607, and TMC-310911.

HIV Reverse Transcriptase Inhibitors

Examples of HIV non-nucleoside or non-nucleotide inhibitors of reversetranscriptase include dapivirine, delavirdine, delavirdine mesylate,doravirine, efavirenz, etravirine, lentinan, MK-8583, nevirapine,rilpivirine, TMC-278LA, ACC-007, AIC-292, KM-023, PC-1005, andelsulfavirine (VM-1500).

Examples of HIV nucleoside or nucleotide inhibitors of reversetranscriptase include adefovir, adefovir dipivoxil, azvudine,emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamidefumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil,tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, VIDEX®and VIDEX EC® (didanosine, ddl), abacavir, abacavir sulfate, alovudine,apricitabine, censavudine, didanosine, elvucitabine, festinavir,fosalvudine tidoxil, CMX-157, dapivirine, doravirine, etravirine,OCR-5753, tenofovir disoproxil orotate, fozivudine tidoxil, islatravir,lamivudine, phosphazid, stavudine, zalcitabine, zidovudine, rovafoviretalafenamide (GS-9131), GS-9148, MK-8504, MK-8591, MK-858, VM-2500 andKP-1461.

HIV Integrase Inhibitors

Examples of HIV integrase inhibitors include elvitegravir, curcumin,derivatives of curcumin, chicoric acid, derivatives of chicoric acid,3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid,aurintricarboxylic acid, derivatives of aurintricarboxylic acid, caffeicacid phenethyl ester, derivatives of caffeic acid phenethyl ester,tyrphostin, derivatives of tyrphostin, quercetin, derivatives ofquercetin, raltegravir, dolutegravir, JTK-351, bictegravir, AVX-15567,BMS-986197, cabotegravir (long-acting injectable), diketo quinolin-4-1derivatives, integrase-LEDGF inhibitor, ledgins, M-522, M-532,NSC-310217, NSC-371056, NSC-48240, NSC-642710, NSC-699171, NSC-699172,NSC-699173, NSC-699174, stilbenedisulfonic acid, T-169 and cabotegravir.

Examples of HIV non-catalytic site, or allosteric, integrase inhibitors(NCINI) include CX-05045, CX-05168, and CX-14442.

HIV Entry Inhibitors

Examples of HIV entry (fusion) inhibitors include cenicriviroc, CCR5inhibitors, gp41 inhibitors, CD4 attachment inhibitors, DS-003(BMS-599793), gp120 inhibitors, and CXCR4 inhibitors.

Examples of CCR5 inhibitors include aplaviroc, vicriviroc, maraviroc,cenicriviroc, leronlimab (PRO-140), adaptavir (RAP-101), nifeviroc(TD-0232), anti-GP120/CD4 or CCR5 bispecific antibodies, B-07, MB-66,polypeptide C₂₅P, TD-0680, and vMIP (Haimipu).

Examples of gp41 inhibitors include albuvirtide, enfuvirtide,BMS-986197, enfuvirtide biobetter, enfuvirtide biosimilar, HIV-1 fusioninhibitors (P26-Bapc), ITV-1, ITV-2, ITV-3, ITV-4, PIE-12 trimer andsifuvirtide.

Examples of CD4 attachment inhibitors include ibalizumab and CADAanalogs.

Examples of gp120 inhibitors include Radha-108 (receptol) 3B3-PE38,BanLec, bentonite-based nanomedicine, fostemsavir tromethamine,IQP-0831, and BMS-663068.

Examples of CXCR4 inhibitors include plerixafor, ALT-1188, N15 peptide,and vMIP (Haimipu).

HIV Maturation Inhibitors

Examples of HIV maturation inhibitors include BMS-955176, BMS-986197,GSK-3640254 and GSK-2838232.

Latency Reversing Agents

Examples of latency reversing agents include histone deacetylase (HDAC)inhibitors, proteasome inhibitors such as velcade, and ixazomib citrate,protein kinase C (PKC) activators, Smyd2 inhibitors, BET-bromodomain 4(BRD4) inhibitors, ionomycin, PMA, SAHA (suberanilohydroxamic acid, orsuberoyl, anilide, and hydroxamic acid), AM-0015, ALT-803, NIZ-985,NKTR-255, IL-15 modulating antibodies, JQ1, disulfiram, amphotericin B,and ubiquitin inhibitors such as largazole analogs, APH-0812, andGSK-343.

Examples of HDAC inhibitors include romidepsin, vorinostat, andpanobinostat.

Examples of PKC activators include indolactam, prostratin, ingenol B,and DAG-lactones.

Capsid Inhibitors

Examples of capsid inhibitors include capsid polymerization inhibitorsor capsid disrupting compounds, HIV nucleocapsid p7 (NCp7) inhibitorssuch as azodicarbonamide, HIV p24 capsid protein inhibitors, GS-6207,AVI-621, AVI-101, AVI-201, AVI-301, and AVI-CAN1-15 series.

HIV Long Acting Agents

Examples of drugs that are being developed as long acting regimens:cabotegravir LA, rilpivirine LA, cabotegravir LA+rilpivirine LA, anyintegrase LA, VM-1500A-LAI, maraviroc (LAI), tenofovir implant, MK-8591implant, long-acting dolutegravir, long acting raltegravir+lamivudine.

Immune-Based Therapies

Examples of immune-based therapies include toll-like receptorsmodulators such as TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9,TLR10, TLR11, TLR12, and TLR13; programmed cell death protein 1 (Pd-1)modulators; programmed death-ligand 1 (Pd-L1) modulators; IL-15modulators; DermaVir; interleukin-7; plaquenil (hydroxychloroquine);proleukin (aldesleukin, IL-2); interferon alfa; interferon alfa-2b;interferon alfa-n3; pegylated interferon alfa; interferon gamma;hydroxyurea; mycophenolate mofetil (MPA) and its ester derivativemycophenolate mofetil (MMF); ribavirin; rintatolimod, polymerpolyethyleneimine (PEI); gepon; rintatolimod; IL-12; WF-10; VGV-1;MOR-22; BMS-936559; CYT-107; interleukin-15/Fc fusion protein; AM-0015,ALT-803, NIZ-985, NKTR-255, NKTR-262, NKTR-214, normferon; peginterferonalfa-2a; peginterferon alfa-2b; recombinant interleukin-15; Xmab-24306,RPI-MN; GS-9620; STING modulators; RIG-I modulators; NOD2 modulators;STING modulators, RIG-I modulators, NOD2 modulators, SB-9200, andIR-103.

Examples of TLR agonists include vesatolimod (GS-9620), GS-986, IR-103,lefitolimod, tilsotolimod, rintatolimod, DSP-0509, AL-034, G-100,cobitolimod, AST-008, motolimod, GSK-1795091, GSK-2245035, VTX-1463,GS-9688, LHC-165, BDB-001, RG-7854, telratolimod, RO-7020531.

Examples of TLR8 modulators include motolimod, resiquimod, 3M-051,3M-052, MCT-465, IMO-4200, VTX-763, VTX-1463 and those disclosed inUS20140045849 (Janssen), US20140073642 (Janssen), WO2014/056953(Janssen), WO2014/076221 (Janssen), WO2014/128189 (Janssen),US20140350031 (Janssen), WO2014/023813 (Janssen), US20080234251 (ArrayBiopharma), US20080306050 (Array Biopharma), US20100029585 (VentirxPharma), US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma),US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma),US20140066432 (Ventirx Pharma), US20140088085 (VentirxPharma),US20140275167 (Novira therapeutics), US20130251673 (Noviratherapeutics), U.S. Pat. No. 9,670,205 (Gilead Sciences Inc.),US20160289229 (Gilead Sciences Inc.), U.S. patent application Ser. No.15/692,161 (Gilead Sciences Inc.), and U.S. patent application Ser. No.15/692,093 (Gilead Sciences Inc.)

Phosphatidylinositol 3-kinase (PI3K) Inhibitors

Examples of PI3K inhibitors include idelalisib, alpelisib, buparlisib,CAI orotate, copanlisib, duvelisib, gedatolisib, neratinib, panulisib,perifosine, pictilisib, pilaralisib, puquitinib mesylate, rigosertib,rigosertib sodium, sonolisib, taselisib, AMG-319, AZD-8186, BAY-1082439,CLR-1401, CLR-457, CUDC-907, DS-7423, EN-3342, GSK-2126458, GSK-2269577,GSK-2636771, INCB-040093, LY-3023414, MLN-1117, PQR-309, RG-7666,RP-6530, RV-1729, SAR-245409, SAR-260301, SF-1126, TGR-1202, UCB-5857,VS-5584, XL-765, and ZSTK-474.

alpha-4/beta-7 Antagonists

Examples of Integrin alpha-4/beta-7 antagonists include PTG-100,TRK-170, abrilumab, etrolizumab, carotegrast methyl, and vedolizumab.

HIV Antibodies, Bispecific Antibodies, and “Antibody-Like” TherapeuticProteins

Examples of HIV antibodies, bispecific antibodies, and “antibody-like”therapeutic proteins include DARTs®, DUOBODIES®, BITES®, XmAbs®,TandAbs®, Fab derivatives, bispecific antibodies, trispecificantibodies, multivalent antibodies, bnABs (broadly neutralizing HIV-1antibodies), BMS-936559, TMB-360, and those targeting HIV gp120 or gp41,antibody-Recruiting Molecules targeting HIV, anti-CD63 monoclonalantibodies, CD3 bispecific antibodies, CD16 bispecific antibodies,anti-GB virus C antibodies, anti-GP120/CD4, CCR5 bispecific antibodies,anti-nef single domain antibodies, anti-Rev antibody, camelid derivedanti-CD18 antibodies, camelid-derived anti-ICAM-1 antibodies, DCVax-001,gp140 targeted antibodies, gp41-based HIV therapeutic antibodies, humanrecombinant mAbs (PGT-121), ibalizumab, Immuglo, and MB-66.

Further examples include bavituximab, UB-421, C2F5, 2G12, C4E10,C2F5+C2G12+C4E10, 8ANC195, 3BNC117, 3BNC117-LS, D1D2, 3BNC60, 10-1074,10-1074-LS, GS-9722, DH411-2, BG18, PGT145, PGT121, PGT122, PGT-151,PGT-133, PGT-135, PGT-128, MDXO10 (ipilimumab), DH511, DH511-2, N6,N6LS, N49P6, N49P7, N49P7.1, N49P9, N49P11, N60P1.1, N60P25.1, N60P2.1,N60P31.1, N60P22, NIH 45-46, PG9, PG16, 8ANC195, 2Dm2m, 4Dm2m, 6Dm2m,VRC01, VRC-01-LS, PGDM1400, A32, 7B2, 10E8, 10E8VLS, 3810109, 10E8v4,10E8.4/iMab, VRC-01/PGDM-1400/10E8v4, IMC-HIV, iMabm36,10E8v4/PGT121-VRC01, eCD4-Ig, IOMA, CAP256-VRC26.25, DRVIA7, SAR-441236,VRC-07-523, VRC07-523LS, VRC-HIVMAB080-00-AB, VRC-HIVMAB060-00-AB,P2G12, and VRC07. Example of HIV bispecific antibodies include MGD014,TMB-bispecific.

Additional examples of HIV bispecific antibodies include MGD014.

Pharmacokinetic Enhancers

Examples of pharmacokinetic enhancers include cobicistat and ritonavir.

HIV Vaccines

Examples of HIV vaccines include peptide vaccines, recombinant subunitprotein vaccines, live vector vaccines using viral vectors such asarenavirus, lymphocytic choriomeningitis virus (LCMV), pichinde virus,modified vaccinia Ankara virus (MVA), adenovirus, adeno-associated virus(AAV), vesicular stomatitis virus (VSV) and Chimpanzee adenovirus(ChAd), DNA vaccines, CD4-derived peptide vaccines, vaccinecombinations, BG505 SOSIP.664 gp140, rgp120 (AIDSVAX), ALVAC HIV,(vCP1521)/AIDSVAX B/E (gp120) (RV144), monomeric gp120 HIV-1 subtype Cvaccine, Remune, ITV-1, Contre Vir, Ad4-Env145NFL, Ad5-ENVA-48, HB-500,DCVax-001 (CDX-2401), Vacc-4x, Vacc-C₅, Vacc-CRX, VVX-004, VAC-3S,multiclade DNA recombinant adenovirus-5 (rAd5), rAd5 gag-pol env A/B/Cvaccine, Pennvax-G, Pennvax-GP/MVA-CMDR, HIV-TriMix-mRNA vaccine,HIV-LAMP-vax, Ad35, Ad35-GRIN, NAcGM3/VSSP ISA-51, poly-ICLC adjuvantedvaccines, TatImmune, GTU-multiHIV (FIT-06), gp140[delta]V2.TV1+MF-59,rVSVIN HIV-1 gag vaccine, SeV-Gag vaccine, AT-20, DNK-4, ad35-Grin/ENV,TBC-M4, HIVAX, HIVAX-2, NYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA-HIV-PT123,rAAV1-PG9DP, GOVX-B11, GOVX-B21, TVI-HIV-1, Ad-4 (Ad4-env CladeC+Ad4-mGag), Paxvax, EN41-UGR7C, EN41-FPA2, PreVaxTat, AE-H, MYM-V101,CombiHIVvac, ADVAX, MYM-V201, MVA-CMDR, DNA-Ad5 gag/pol/nef/nev(HVTN505), MVATG-17401, ETV-01, CDX-1401, rcAD26.MOS1.HIV-Env,Ad26.Mod.HIV vaccine, Ad26.Mod.HIV+MVA mosaic vaccine+gp140, AGS-004,AVX-101, AVX-201, PEP-6409, SAV-001, ThV-01, TL-01, TUTI-16, VGX-3300,IHV-001, and virus-like particle vaccines such as pseudovirion vaccine,CombiVICHvac, LFn-p24 B/C fusion vaccine, GTU-based DNA vaccine, HIVgag/pol/nef/env DNA vaccine, anti-TAT HIV vaccine, conjugatepolypeptides vaccine, dendritic-cell vaccines, gag-based DNA vaccine,GI-2010, gp41 HIV-1 vaccine, HIV vaccine (PIKA adjuvant), I i-key/MHCclass II epitope hybrid peptide vaccines, ITV-2, ITV-3, ITV-4, LIPO-5,multiclade Env vaccine, MVA vaccine, Pennvax-GP, pp71-deficient HCMVvector HIV gag vaccine, recombinant peptide vaccine (HIV infection),NCI, rgp160 HIV vaccine, RNActive HIV vaccine, SCB-703, Tat Oyi vaccine,TBC-M4, therapeutic HIV vaccine, UBI HIV gp120, Vacc-4x+romidepsin,variant gp120 polypeptide vaccine, rAd5 gag-pol env A/B/C vaccine,DNA.HTI, DNA.HTI and MVA.HTI, VRC-HIVDNA016-00-VP+VRC-HIVADV014-00-VP,INO-6145, JNJ-9220, gp145 C.6980; eOD-GT8 60mer based vaccine,PD-201401, env (A, B, C, A/E)/gag (C) DNA Vaccine, gp120 (A,B,C,A/E)protein vaccine, PDPHV-201401, Ad4-EnvCN54, EnvSeq-1 Envs HIV-1 vaccine(GLA-SE adjuvanted), HIV p24gag prime-boost plasmid DNA vaccine,arenavirus vector-based immunotherapies (Vaxwave, TheraT), MVA-BN HIV-1vaccine regimen, MVA.tHIVconsv4, MVA.tHIVconsv3, UBI HIV gp120, mRNAbased prophylactic vaccines, TBL-1203HI, VRC-HIVRGP096-00-VP, VAX-3S,HIV MAG DNA vaccine.

Additional HIV Therapeutic Agents

Examples of additional HIV therapeutic agents include the compoundsdisclosed in WO 2004/096286 (Gilead Sciences), WO 2006/015261 (GileadSciences), WO 2006/110157 (Gilead Sciences), WO 2012/003497 (GileadSciences), WO 2012/003498 (Gilead Sciences), WO 2012/145728 (GileadSciences), WO 2013/006738 (Gilead Sciences), WO 2013/159064 (GileadSciences), WO 2014/100323 (Gilead Sciences), US 2013/0165489 (Universityof Pennsylvania), US 2014/0221378 (Japan Tobacco), US 2014/0221380(Japan Tobacco), WO 2009/062285 (Boehringer Ingelheim), WO 2010/130034(Boehringer Ingelheim), WO 2013/006792 (Pharma Resources), US20140221356 (Gilead Sciences), US 20100143301 (Gilead Sciences) and WO2013/091096 (Boehringer Ingelheim).

Examples of other drugs for treating HIV include acemannan, alisporivir,astodrimer, BanLec, CC-11050, deferiprone, Gamimune, griffithsin,metenkefalin, naltrexone, Prolastin, REP 9, RPI-MN, Vorapaxar, VSSP,Hlviral, SB-728-T, 1,5-dicaffeoylquinic acid, rHIV7-shl-TAR-CCR5RZ,AAV-eCD4-Ig gene therapy, MazF gene therapy, MK-8527, BlockAide,PSC-RANTES, ABX-464, AG-1105, APH-0812, BIT-225, CYT-107, HGTV-43,HPH-116, HS-10234, IMO-3100, IND-02, MK-1376, MK-2048, MK-4250, MK-8507,MK-8591, NOV-205, PA-1050040 (PA-040), PGN-007, SCY-635, SB-9200,SCB-719, TR-452, TEV-90110, TEV-90112, TEV-90111, TEV-90113, RN-18,Immuglo, and VIR-576.

Gene Therapy and Cell Therapy

Gene therapy and cell therapy include the genetic modification tosilence a gene; genetic approaches to directly kill the infected cells;the infusion of immune cells designed to replace most of the patient'sown immune system to enhance the immune response to infected cells, oractivate the patient's own immune system to kill infected cells, or findand kill the infected cells; and genetic approaches to modify cellularactivity to further alter endogenous immune responsiveness against theinfection.

Examples of dendritic cell therapy include AGS-004.

Gene Editors

Examples of gene editing systems include a CRISPR/Cas9 system, a zincfinger nuclease system, a TALEN system, a homing endonucleases system,and a meganuclease system.

Examples of HIV targeting CRISPR/Cas9 systems include EBT101.

CAR-T Cell Therapy

CAR-T cell therapy includes a population of immune effector cellsengineered to express a chimeric antigen receptor (CAR), wherein the CARcomprises an HIV antigen-binding domain. The HIV antigens include an HIVenvelope protein or a portion thereof, gp120 or a portion thereof, a CD4binding site on gp120, the CD4-induced binding site on gp120, N glycanon gp120, the V2 of gp120, and the membrane proximal region on gp41. Insome embodiments, the immune effector cell is a T cell or an NK cell. Insome embodiments, the T cell is a CD4+ T cell, a CD8+ T cell, or acombination thereof.

Examples of HIV CAR-T cell therapy include VC-CAR-T, anti-CD4 CART celltherapy, autologous hematopoietic stem cells genetically engineered toexpress a CD4 CAR and the C₄₆ peptide.

TCR-T Cell Therapy

TCR-T cell therapy includes T cells engineered to target HIV derivedpeptides present on the surface of virus-infected cells.

It will be appreciated by one of skill in the art that the additionaltherapeutic agents listed above may be included in more than one of theclasses listed above. The particular classes are not intended to limitthe functionality of those compounds listed in those classes.

In a specific embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with an HIVnucleoside or nucleotide inhibitor of reverse transcriptase and an HIVnon-nucleoside inhibitor of reverse transcriptase. In another specificembodiment, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with an HIV nucleoside ornucleotide inhibitor of reverse transcriptase, and an HIV proteaseinhibiting compound. In an additional embodiment, a compound disclosedherein, or a pharmaceutically acceptable salt thereof, is combined withan HIV nucleoside or nucleotide inhibitor of reverse transcriptase, anHIV non-nucleoside inhibitor of reverse transcriptase, and apharmacokinetic enhancer. In certain embodiments, a compound disclosedherein, or a pharmaceutically acceptable salt thereof, is combined withat least one HIV nucleoside inhibitor of reverse transcriptase, anintegrase inhibitor, and a pharmacokinetic enhancer. In anotherembodiment, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with two HIV nucleoside ornucleotide inhibitors of reverse transcriptase.

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with one, two,three, four or more additional therapeutic agents selected from ATRIPLA®(efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA®(EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, andemtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovirdisoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxilfumarate and emtricitabine; TDF+FTC); DESCOVY® (tenofovir alafenamideand emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, andrilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine,cobicistat, and elvitegravir); BIKTARVY® (bictegravir, emtricitabine,tenofovir alafenamide); adefovir; adefovir dipivoxil; cobicistat;emtricitabine; tenofovir; tenofovir disoproxil; tenofovir disoproxilfumarate; tenofovir alafenamide; tenofovir alafenamide hemifumarate;TRIUMEQ® (dolutegravir, abacavir, and lamivudine); dolutegravir,abacavir sulfate, and lamivudine; raltegravir; raltegravir andlamivudine; maraviroc; enfuvirtide; ALUVIA® (KALETRA®; lopinavir andritonavir); COMBIVIR® (zidovudine and lamivudine; AZT+3TC); EPZICOM®(LIVEXA®; abacavir sulfate and lamivudine; ABC+3TC); TRIZIVIR® (abacavirsulfate, zidovudine, and lamivudine; ABC+AZT+3TC); rilpivirine;rilpivirine hydrochloride; atazanavir sulfate and cobicistat; atazanavirand cobicistat; darunavir and cobicistat; atazanavir; atazanavirsulfate; dolutegravir; elvitegravir; ritonavir; atazanavir sulfate andritonavir; darunavir; lamivudine; prolastin; fosamprenavir;fosamprenavir calcium efavirenz; etravirine; nelfinavir; nelfinavirmesylate; interferon; didanosine; stavudine; indinavir; indinavirsulfate; tenofovir and lamivudine; zidovudine; nevirapine; saquinavir;saquinavir mesylate; aldesleukin; zalcitabine; tipranavir; amprenavir;delavirdine; delavirdine mesylate; Radha-108 (receptol); lamivudine andtenofovir disoproxil fumarate; efavirenz, lamivudine, and tenofovirdisoproxil fumarate; phosphazid; lamivudine, nevirapine, and zidovudine;abacavir; and abacavir sulfate.

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with abacavirsulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate,tenofovir disoproxil hemifumarate, tenofovir alafenamide, tenofoviralafenamide hemifumarate, or bictegravir.

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with tenofovir,tenofovir disoproxil, tenofovir disoproxil fumarate, tenofoviralafenamide, tenofovir alafenamide hemifumarate, or bictegravir.

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with a firstadditional therapeutic agent selected from the group consisting ofabacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxilfumarate, tenofovir alafenamide, tenofovir alafenamide hemifumarate, andbictegravir and a second additional therapeutic agent selected from thegroup consisting of emtricitabine and lamivudine.

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with a firstadditional therapeutic agent selected from the group consisting oftenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate,tenofovir alafenamide, tenofovir alafenamide hemifumarate, andbictegravir and a second additional therapeutic agent, wherein thesecond additional therapeutic agent is emtricitabine.

A compound as disclosed herein may be combined with one or moreadditional therapeutic agents in any dosage amount of the compound(e.g., from 1 mg to 500 mg of compound).

In certain embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with 5-30 mgtenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, ortenofovir alafenamide, and 200 mg emtricitabine. In certain embodiments,a compound disclosed herein, or a pharmaceutically acceptable saltthereof, is combined with 5-10, 5-15, 5-20, 5-25, 25-30, 20-30, 15-30,or 10-30 mg tenofovir alafenamide fumarate, tenofovir alafenamidehemifumarate, or tenofovir alafenamide, and 200 mg emtricitabine. Incertain embodiments, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with 10 mg tenofovir alafenamidefumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide,and 200 mg emtricitabine. In certain embodiments, a compound disclosedherein, or a pharmaceutically acceptable salt thereof, is combined with25 mg tenofovir alafenamide fumarate, tenofovir alafenamidehemifumarate, or tenofovir alafenamide, and 200 mg emtricitabine. Acompound as disclosed herein (e.g., a compound of Formula I, I-Z, I-E,II-Z, IIa-Z, IIb-Z, III-Z, or IIIa-Z) may be combined with the agentsprovided herein in any dosage amount of the compound (e.g., from 1 mg to500 mg of compound) as if each combination of dosages were specificallyand individually listed.

In certain embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with 200-400 mgtenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, ortenofovir disoproxil, and 200 mg emtricitabine. In certain embodiments,a compound disclosed herein, or a pharmaceutically acceptable saltthereof, is combined with 200-250, 200-300, 200-350, 250-350, 250-400,350-400, 300-400, or 250-400 mg tenofovir disoproxil fumarate, tenofovirdisoproxil hemifumarate, or tenofovir disoproxil, and 200 mgemtricitabine. In certain embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with 300 mgtenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, ortenofovir disoproxil, and 200 mg emtricitabine. A compound as disclosedherein (e.g., a compound of Formula I, I-Z, I-E, II-Z, IIa-Z, IIb-Z,III-Z, or IIIa-Z) may be combined with the agents provided herein in anydosage amount of the compound (e.g., from 1 mg to 500 mg of compound) asif each combination of dosages were specifically and individuallylisted.

Cancer and/or Hyper-Proliferative Disease Combination Therapy

In one embodiment, the compound provided herein may be employed withother therapeutic methods of cancer treatment. Preferably, combinationtherapy with chemotherapeutic, hormonal, antibody, surgical and/orradiation treatments are contemplated.

In some embodiments, the further anti-cancer therapy is surgery and/orradiotherapy. In some embodiments, the further anti-cancer therapy is atleast one additional cancer medicament.

In some embodiments, there is provided a combination comprising acompound of Formula I, I-Z, I-E, II-Z, IIa-Z, IIb-Z, III-Z, or IIIa-Z,or a pharmaceutically acceptable salt thereof and at least one furthercancer medicament.

In some embodiments, there is provided a combination comprising acompound of Formula I, I-Z, I-E, II-Z, IIa-Z, IIb-Z, III-Z, or IIIa-Z,or a pharmaceutically acceptable salt thereof and at least one furthercancer medicament, for use in therapy.

In some embodiments, there is provided the use of a combinationcomprising a compound of Formula I, I-Z, I-E, II-Z, IIa-Z, IIb-Z, III-Z,or IIIa-Z, or a pharmaceutically acceptable salt thereof and at leastone cancer medicament, in the manufacture of a medicament for thetreatment of cancer.

Examples of further cancer medicaments include intercalating substancessuch as anthracycline, doxorubicin, idarubicin, epirubicin, anddaunorubicin; topoisomerase inhibitors such as irinotecan, topotecan,camptothecin, lamellarin D, etoposide, teniposide, mitoxantrone,amsacrine, ellipticines and aurintricarboxylic acid; nitrosoureacompounds such as carmustine (BCNU), lomustine (CCNU), and streptozocin;nitrogen mustards such as cyclophosphamide, mechlorethamine, uramustine,bendamustine, melphalan, chlorambucil, mafosfamide, trofosfamid andifosfamide; alkyl sulfonates such as busulfan and treosulfan; alkylatingagents such as procarbazin, dacarbazin, temozolomid and thiotepa;platinum analogues such as cisplatin, carboplatin, nedaplatin,oxaliplatin, satraplatin, and triplatin tetranitrate; microtubuledisruptive drugs such as vinblastine, colcemid and nocodazole;antifolates like methotrexate, aminopterin, dichloromethotrexat,pemetrexed, raltitrexed and pralatrexate: purine analogues likeazathioprine, mercaptopurine, thioguanine, fludarabine, fludarabinephosphate, pentostatin and cladribine; pyrimidine analogues like5-fluorouracil, floxuridine, cytarabine, 6-azauracil, gemcitabine;steroids such as gestagene, androgene, glucocorticoids, dexamethasone,prednisolone, and prednisone; anti-cancer antibodies such as monoclonalantibodies, e.g., alemtuzumab, apolizumab, cetuximab, epratuzumab,galiximab, gemtuzumab, ipilimumab, labetuzumab, panitumumab, rituximab,trastuzumab, nimotuzumab, mapatumumab, matuzumab, rhMab ICR62 andpertuzumab, radioactively labeled antibodies and antibody-drugconjugates; anti-cancer peptides such as radioactively labeled peptidesand peptide-drug conjugates; and taxane and taxane analogues such aspaclitaxel and docetaxel.

In certain embodiments, a method for treating or preventing a cancer orhyper-proliferative disease in a human or animal having or at risk ofhaving the cancer or hyper-proliferative disease is provided, comprisingadministering to the human or animal a therapeutically effective amountof a compound of Formula I, I-Z, I-E, II-Z, IIa-Z, IIb-Z, III-Z, orIIIa-Z as disclosed herein, or a pharmaceutically acceptable saltthereof, in combination with a therapeutically effective amount of oneor more (e.g., one, two, three, one or two, or one to three) additionaltherapeutic agents. In one embodiment, a method for treating a cancer orhyper-proliferative disease in a human or animal having or at risk ofhaving the cancer or hyper-proliferative disease is provided, comprisingadministering to the human or animal a therapeutically effective amountof a compound disclosed herein, or a pharmaceutically acceptable saltthereof, in combination with a therapeutically effective amount of oneor more (e.g., one, two, three, one or two, or one to three) additionaltherapeutic agents.

In certain embodiments, the present disclosure provides a method fortreating a cancer or hyper-proliferative disease, comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a compound disclosed herein, or a pharmaceutically acceptablesalt thereof, in combination with a therapeutically effective amount ofone or more additional therapeutic agents which are suitable fortreating cancer or hyper-proliferative disease.

The compounds described herein may be used or combined with one or moreof a chemotherapeutic agent, an anti-cancer agent, an anti-angiogenicagent, an anti-fibrotic agent, an immunotherapeutic agent, a therapeuticantibody, a bispecific antibody and “antibody-like” therapeutic protein(such as DARTs®, Duobodies®, Bites®, XmAbs®, TandAbs @, Fabderivatives), an antibody-drug conjugate (ADC), a radiotherapeuticagent, an anti-neoplastic agent, an anti-proliferation agent, anoncolytic virus, a gene modifier or editor (such as CRISPR/Cas9, zincfinger nucleases or synthetic nucleases, TALENs), a CAR (chimericantigen receptor) T-cell immunotherapeutic agent, an engineered T cellreceptor (TCR-T), or any combination thereof. These therapeutic agentsmay be in the forms of compounds, antibodies, polypeptides, orpolynucleotides. In one embodiment, provided herein is a productcomprising a compound described herein and an additional therapeuticagent as a combined preparation for simultaneous, separate, orsequential use in therapy.

The one or more additional therapeutic agents include, but are notlimited to, an inhibitor, agonist, antagonist, ligand, modulator,stimulator, blocker, activator or suppressor of a gene, ligand,receptor, protein, or factor. Non-limiting examples of additionaltherapeutic agents include:

-   -   Abelson murine leukemia viral oncogene homolog 1 gene (ABL, such        as ABL1), Acetyl-CoA carboxylase (such as ACC1/2), activated CDC        kinase (ACK, such as ACKI), Adenosine deaminase, adenosine        receptor (such as A2B, A2a, A3), Adenylate cyclase, ADP ribosyl        cyclase-1, adrenocorticotropic hormone receptor (ACTH),        Aerolysin, AKT1 gene, Alk-5 protein kinase, Alkaline        phosphatase, Alpha 1 adrenoceptor, Alpha 2 adrenoceptor,        Alpha-ketoglutarate dehydrogenase (KGDH), Aminopeptidase N, AMP        activated protein kinase, anaplastic lymphoma kinase (ALK, such        as ALKI), Androgen receptor, Angiopoietin (such as ligand-1,        ligand-2), Angiotensinogen (AGT) gene, murine thymoma viral        oncogene homolog 1 (AKT) protein kinase (such as AKT1, AKT2,        AKT3), apolipoprotein A-I (APOA1) gene, Apoptosis inducing        factor, apoptosis protein (such as 1, 2), apoptosis        signal-regulating kinase (ASK, such as ASKI), Arginase (I),        Arginine deiminase, Aromatase, Asteroid homolog 1 (ASTE1) gene,        ataxia telangiectasia and Rad 3 related (ATR) serine/threonine        protein kinase, Aurora protein kinase (such as 1, 2), Axl        tyrosine kinase receptor, Baculoviral IAP repeat containing 5        (BIRC5) gene, Basigin, B-cell lymphoma 2 (BCL2) gene, Bcl2        binding component 3, Bcl2 protein, BCL2L11 gene, BCR (breakpoint        cluster region) protein and gene, Beta adrenoceptor,        Beta-catenin, B-lymphocyte antigen CD19, B-lymphocyte antigen        CD20, B-lymphocyte cell adhesion molecule, B-lymphocyte        stimulator ligand, Bone morphogenetic protein-10 ligand, Bone        morphogenetic protein-9 ligand modulator, Brachyury protein,        Bradykinin receptor, B-Raf proto-oncogene (BRAF), Brc-Abl        tyrosine kinase, Bromodomain and external domain (BET)        bromodomain containing protein (such as BRD2, BRD3, BRD4),        Bruton's tyrosine kinase (BTK), Calmodulin, calmodulin-dependent        protein kinase (CaMK, such as CAMKII), Cancer testis antigen 2,        Cancer testis antigen NY-ESO-1, cancer/testis antigen 1B (CTAG1)        gene, Cannabinoid receptor (such as CB1, CB2), Carbonic        anhydrase, casein kinase (CK, such as CKI, CKII), Caspase (such        as caspase-3, caspase-7, Caspase-9), caspase 8 apoptosis-related        cysteine peptidase CASP8-FADD-like regulator, Caspase        recruitment domain protein-15, Cathepsin G, CCR5 gene,        CDK-activating kinase (CAK), Checkpoint kinase (such as CHK1,        CHK2), chemokine (C—C motif) receptor (such as CCR2, CCR4, CCR5,        CCR8), chemokine (C-X-C motif) receptor (such as CXCR4, CXCR1        and CXCR2), Chemokine CC21 ligand, Cholecystokinin CCK2        receptor, Chorionic gonadotropin, c-Kit (tyrosine-protein kinase        Kit or CD117), CISH (Cytokine-inducible SH2-containing protein),        Claudin (such as 6, 18), cluster of differentiation (CD) such as        CD4, CD27, CD29, CD30, CD33, CD37, CD40, CD40 ligand receptor,        CD40 ligand, CD40LG gene, CD44, CD45, CD47, CD49b, CD51, CD52,        CD55, CD58, CD66e, (CEACAM6), CD70 gene, CD74, CD79, CD79b,        CD79B gene, CD80, CD95, CD99, CD117, CD122, CDw123, CD134,        CDw137, CD158a, CD158b1, CD158b2, CD223, CD276 antigen;        clusterin (CLU) gene, Clusterin, c-Met (hepatocyte growth factor        receptor (HGFR)), Complement C₃, Connective tissue growth        factor, COP9 signalosome subunit 5, CSF-1 (colony-stimulating        factor 1 receptor), CSF2 gene, CTLA-4 (cytotoxic T-lymphocyte        protein 4) receptor, C-type lectin domain protein 9A (CLEC9A),        Cyclin D1, Cyclin G1, cyclin-dependent kinases (CDK, such as        CDK1, CDK1B, CDK2-9), cyclooxygenase (such as COX1, COX2),        CYP2B1 gene, Cysteine palmitoyltransferase porcupine, Cytochrome        P450 11B2, Cytochrome P450 17, cytochrome P450 17A1, Cytochrome        P450 2D6, cytochrome P450 3A4, Cytochrome P450 reductase,        cytokine signalling-1, cytokine signalling-3, Cytoplasmic        isocitrate dehydrogenase, Cytosine deaminase, cytosine DNA        methyltransferase, cytotoxic T-lymphocyte protein-4, DDR2 gene,        Death receptor 5 (DR5, TRAILR2), Death receptor 4 (DR4,        TRAILR1), Delta-like protein ligand (such as 3, 4),        Deoxyribonuclease, Dickkopf-1 ligand, dihydrofolate reductase        (DHFR), Dihydropyrimidine dehydrogenase, Dipeptidyl peptidase        IV, discoidin domain receptor (DDR, such as DDR1), DNA binding        protein (such as HU-beta), DNA dependent protein kinase, DNA        gyrase, DNA methyltransferase, DNA polymerase (such as alpha),        DNA primase, dUTP pyrophosphatase, L-dopachrome tautomerase,        echinoderm microtubule like protein 4, EGFR tyrosine kinase        receptor, Elastase, Elongation factor 1 alpha 2, Elongation        factor 2, Endoglin, Endonuclease, Endoplasmin, Endosialin,        Endostatin, endothelin (such as ET-A, ET-B), Enhancer of zeste        homolog 2 (EZH2), Ephrin (EPH) tyrosine kinase (such as Epha3,        Ephb4), Ephrin B2 ligand, epidermal growth factor, epidermal        growth factor receptors (EGFR), epidermal growth factor receptor        (EGFR) gene, Epigen, Epithelial cell adhesion molecule (EpCAM),        Erb-b2 (v-erb-b2 avian erythroblastic leukemia viral oncogene        homolog 2) tyrosine kinase receptor, Erb-b3 tyrosine kinase        receptor, Erb-b4 tyrosine kinase receptor, E-selectin, Estradiol        17 beta dehydrogenase, Estrogen receptor (such as alpha, beta),        Estrogen related receptor, Eukaryotic translation initiation        factor 5A (EIF5A) gene, Exportin 1, Extracellular signal related        kinase (such as 1, 2), Extracellular signal-regulated kinases        (ERK), Factor (such as Xa, VIIa), farnesoid x receptor (FXR),        Fas ligand, Fatty acid synthase, (FASN), Ferritin, FGF-2 ligand,        FGF-5 ligand, fibroblast growth factor (FGF, such as FGF1, FGF2,        FGF4), Fibronectin, Fms-related tyrosine kinase 3 (Flt3),        Fms-like tyrosine kinase-3 ligand (FLT3L), focal adhesion kinase        (FAK, such as FAK2), folate hydrolase prostate-specific membrane        antigen 1 (FOLH1), Folate receptor (such as alpha), Folate,        Folate transporter 1, FYN tyrosine kinase, paired basic amino        acid cleaving enzyme (FURIN), Beta-glucuronidase,        Galactosyltransferase, Galectin-3, Ganglioside GD2,        Glucocorticoid, glucocorticoid-induced TNFR-related protein GITR        receptor, Glutamate carboxypeptidase II, glutaminase,        Glutathione S-transferase P, glycogen synthase kinase (GSK, such        as 3-beta), Glypican 3 (GPC3), gonadotropin-releasing hormone        (GNRH), Granulocyte macrophage colony stimulating factor        (GM-CSF) receptor, Granulocyte-colony stimulating factor (GCSF)        ligand, growth factor receptor-bound protein 2 (GRB2), Grp78 (78        kDa glucose-regulated protein) calcium binding protein,        molecular chaperone groEL2 gene, Heme oxygenase 1 (HO1), Heme        oxygenase 2 (H02), Heat shock protein (such as 27, 70, 90 alpha,        beta), Heat shock protein gene, Heat stable enterotoxin        receptor, Hedgehog protein, Heparanase, Hepatocyte growth        factor, HERV-H LTR associating protein 2, Hexose kinase,        Histamine H2 receptor, Histone methyltransferase (DOT1L),        histone deacetylase (HDAC, such as 1, 2, 3, 6, 10, 11), Histone        H1, Histone H3, HLA class I antigen (A-2 alpha), HLA class II        antigen, HLA class I antigen alpha G (HLA-G), Non-classical HLA,        Homeobox protein NANOG, HSPB1 gene, Human leukocyte antigen        (HLA), Human papillomavirus (such as E6, E7) protein, Hyaluronic        acid, Hyaluronidase, Hypoxia inducible factor-1 alpha (HIFIl),        Imprinted Maternally Expressed Transcript (H19) gene,        mitogen-activated protein kinase 1 (MAP4K1), tyrosine-protein        kinase HCK, I-Kappa-B kinase (IKK, such as IKKbe), IL-1 alpha,        IL-1 beta, IL-12, IL-12 gene, IL-15, IL-17, IL-2 gene, IL-2        receptor alpha subunit, IL-2, IL-3 receptor, IL-4, IL-6, IL-7,        IL-8, immunoglobulin (such as G, G1, G2, K, M), Immunoglobulin        Fc receptor, Immunoglobulin gamma Fc receptor (such as I, III,        IIIA), indoleamine 2,3-dioxygenase (IDO, such as IDO1 and IDO2),        indoleamine pyrrole 2,3-dioxygenase 1 inhibitor, insulin        receptor, Insulin-like growth factor (such as 1, 2), Integrin        alpha-4/beta-1, integrin alpha-4/beta-7, Integrin        alpha-5/beta-1, Integrin alpha-V/beta-3, Integrin        alpha-V/beta-5, Integrin alpha-V/beta-6, Intercellular adhesion        molecule 1 (ICAM-1), interferon (such as alpha, alpha 2, beta,        gamma), Interferon inducible protein absent in melanoma 2        (AIM2), interferon type I receptor, Interleukin 1 ligand,        Interleukin 13 receptor alpha 2, interleukin 2 ligand,        interleukin-1 receptor-associated kinase 4 (IRAK4),        Interleukin-2, Interleukin-29 ligand, isocitrate dehydrogenase        (such as IDH1, IDH2), Janus kinase (JAK, such as JAK1, JAK2),        Jun N terminal kinase, kallikrein-related peptidase 3 (KLK3)        gene, Killer cell Ig like receptor, Kinase insert domain        receptor (KDR), Kinesin-like protein KIF11, Kirsten rat sarcoma        viral oncogene homolog (KRAS) gene, Kisspeptin (KiSS-1)        receptor, KIT gene, v-kit Hardy-Zuckerman 4 feline sarcoma viral        oncogene homolog (KIT) tyrosine kinase, lactoferrin,        Lanosterol-14 demethylase, LDL receptor related protein-1,        Leukocyte immunoglobulin-like receptor subfamily B member 1        (ILT2), Leukocyte immunoglobulin-like receptor subfamily B        member 2 (ILT4), Leukotriene A4 hydrolase, Listeriolysin,        L-Selectin, Luteinizing hormone receptor, Lyase, lymphocyte        activation gene 3 protein (LAG-3), Lymphocyte antigen 75,        Lymphocyte function antigen-3 receptor, lymphocyte-specific        protein tyrosine kinase (LCK), Lymphotactin, Lyn (Lck/Yes novel)        tyrosine kinase, lysine demethylases (such as KDM1, KDM2, KDM4,        KDM5, KDM6, A/B/C/D), Lysophosphatidate-1 receptor,        lysosomal-associated membrane protein family (LAMP) gene, Lysyl        oxidase homolog 2, lysyl oxidase protein (LOX), lysyl        oxidase-like protein (LOXL, such as LOXL2), 5-Lipoxygenase        (5-LOX), Hematopoietic Progenitor Kinase 1 (HPK1), Hepatocyte        growth factor receptor (MET) gene, macrophage colony-stimulating        factor (MCSF) ligand, Macrophage migration inhibitory fact,        MAGEC1 gene, MAGEC2 gene, Major vault protein, MAPK-activated        protein kinase (such as MK2), Mas-related G-protein coupled        receptor, matrix metalloprotease (MMP, such as MMP2, MMP9),        Mcl-1 differentiation protein, Mdm2 p53-binding protein, Mdm4        protein, Melan-A (MART-1) melanoma antigen, Melanocyte protein        Pmel 17, melanocyte stimulating hormone ligand, melanoma antigen        family A3 (MAGEA3) gene, Melanoma associated antigen (such as 1,        2, 3, 6), Membrane copper amine oxidase, Mesothelin, MET        tyrosine kinase, Metabotropic glutamate receptor 1,        Metalloreductase STEAP1 (six transmembrane epithelial antigen of        the prostate 1), Metastin, methionine aminopeptidase-2,        Methyltransferase, Mitochondrial 3 ketoacyl CoA thiolase,        mitogen-activate protein kinase (MAPK), mitogen-activated        protein kinase (MEK, such as MEK1, MEK2), mTOR (mechanistic        target of rapamycin (serine/threonine kinase), mTOR complex        (such as 1,2), mucin (such as 1, 5A, 16), mut T homolog (MTH,        such as MTH1), Myc proto-oncogene protein, myeloid cell leukemia        1 (MCL1) gene, myristoylated alanine-rich protein kinase C        substrate (MARCKS) protein, NAD ADP ribosyltransferase,        natriuretic peptide receptor C, Neural cell adhesion molecule 1,        Neurokinin 1 (NK1) receptor, Neurokinin receptor, Neuropilin 2,        NF kappa B activating protein, NIMA-related kinase 9 (NEK9),        Nitric oxide synthase, NK cell receptor, NK3 receptor, NKG2 A B        activating NK receptor, NLRP3 (NACHT LRR PYD domain protein 3)        modulators, Noradrenaline transporter, Notch (such as Notch-2        receptor, Notch-3 receptor, Notch-4 receptor), Nuclear erythroid        2-related factor 2, Nuclear Factor (NF) kappa B, Nucleolin,        Nucleophosmin, nucleophosmin-anaplastic lymphoma kinase        (NPM-ALK), 2 oxoglutarate dehydrogenase, 2,5-oligoadenylate        synthetase, O-methylguanine DNA methyltransferase, Opioid        receptor (such as delta), Ornithine decarboxylase, Orotate        phosphoribosyltransferase, orphan nuclear hormone receptor        NR4A1, Osteocalcin, Osteoclast differentiation factor,        Osteopontin, OX-40 (tumor necrosis factor receptor superfamily        member 4 TNFRSF4, or CD134) receptor, P3 protein, p38 kinase,        p38 MAP kinase, p53 tumor suppressor protein, Parathyroid        hormone ligand, peroxisome proliferator-activated receptors        (PPAR, such as alpha, delta, gamma), P-Glycoprotein (such as 1),        phosphatase and tensin homolog (PTEN), phosphatidylinositol        3-kinase (PI3K), phosphoinositide-3 kinase (PI3K such as alpha,        delta, gamma), phosphorylase kinase (PK), PKN3 gene, placenta        growth factor, platelet-derived growth factor (PDGF, such as        alpha, beta), Platelet-derived growth factor (PDGF, such as        alpha, beta), Pleiotropic drug resistance transporter, Plexin        B1, PLKI gene, polo-like kinase (PLK), Polo-like kinase 1, Poly        (ADP ribose) polymerase (PARP, such as PARP1, PARP2, PARP3,        PARP7, and mono-PARPs), Preferentially expressed antigen in        melanoma (PRAME) gene, Prenyl-binding protein (PrPB), Probable        transcription factor PML, Progesterone receptor, Programmed cell        death 1 (PD-1), Programmed cell death ligand 1 inhibitor        (PD-L1), Prosaposin (PSAP) gene, Prostanoid receptor (EP4),        Prostaglandin E2 synthase, prostate specific antigen, Prostatic        acid phosphatase, proteasome, Protein E7, Protein        famesyltransferase, protein kinase (PK, such as A, B, C),        protein tyrosine kinase, Protein tyrosine phosphatase beta,        Proto-oncogene serine/threonine-protein kinase (PIM, such as        PIM-1, PIM-2, PIM-3), P-Selectin, Purine nucleoside        phosphorylase, purinergic receptor P2X ligand gated ion channel        7 (P2X7), Pyruvate dehydrogenase (PDH), Pyruvate dehydrogenase        kinase, Pyruvate kinase (PYK), 5-Alpha-reductase, Raf protein        kinase (such as 1, B), RAF1 gene, Ras gene, Ras GTPase, RET        gene, Ret tyrosine kinase receptor, retinoblastoma associated        protein, retinoic acid receptor (such as gamma), Retinoid X        receptor, Rheb (Ras homolog enriched in brain) GTPase, Rho (Ras        homolog) associated protein kinase 2, ribonuclease,        Ribonucleotide reductase (such as M2 subunit), Ribosomal protein        S6 kinase, RNA polymerase (such as I, II), Ron (Recepteur        d'Origine Nantais) tyrosine kinase, ROS1 (ROS proto-oncogene 1,        receptor tyrosine kinase)gene, RosI tyrosine kinase,        Runt-related transcription factor 3, Gamma-secretase, S100        calcium binding protein A9, Sarco endoplasmic calcium ATPase,        Second mitochondria-derived activator of caspases (SMAC)        protein, Secreted frizzled related protein-2, Secreted        phospholipase A2, Semaphorin-4D, Serine protease,        serine/threonine kinase (STK), serine/threonine-protein kinase        (TBK, such as TBKI), signal transduction and transcription        (STAT, such as STAT-1, STAT-3, STAT-5), Signaling lymphocytic        activation molecule (SLAM) family member 7, six-transmembrane        epithelial antigen of the prostate (STEAP) gene, SL cytokine        ligand, smoothened (SMO) receptor, Sodium iodide cotransporter,        Sodium phosphate cotransporter 2B, Somatostatin receptor (such        as 1, 2, 3, 4, 5), Sonic hedgehog protein, Son of sevenless        (SOS), Specific protein 1 (Sp1) transcription factor,        Sphingomyelin synthase, Sphingosine kinase (such as 1, 2),        Sphingosine-1-phosphate receptor-1, spleen tyrosine kinase        (SYK), SRC gene, Src tyrosine kinase, STAT3 gene, Steroid        sulfatase, Stimulator of interferon genes (STING) receptor,        stimulator of interferon genes protein, Stromal cell-derived        factor 1 ligand, SUMO (small ubiquitin-like modifier),        Superoxide dismutase, Suppressor of cytokine signaling        modulators (SOCS), Survivin protein, Synapsin 3, Syndecan-1,        Synuclein alpha, T cell surface glycoprotein CD28, tank-binding        kinase (TBK), TATA box-binding protein-associated factor RNA        polymerase I subunit B (TAF1B) gene, T-cell CD3 glycoprotein        zeta chain, T-cell differentiation antigen CD6, T-cell        immunoglobulin and mucin-domain containing-3 (TIM-3), T-cell        surface glycoprotein CD8, Tec protein tyrosine kinase, Tek        tyrosine kinase receptor, telomerase, Telomerase reverse        transcriptase (TERT) gene, Tenascin, TGF beta 2 ligand,        Thrombopoietin receptor, Thymidine kinase, Thymidine        phosphorylase, Thymidylate synthase, Thymosin (such as alpha 1),        Thyroid hormone receptor, Thyroid stimulating hormone receptor,        Tissue factor, TNF related apoptosis inducing ligand, TNFR1        associated death domain protein, TNF-related apoptosis-inducing        ligand (TRAIL) receptor, TNFSF11 gene, TNFSF9 gene, Toll-like        receptor (TLR such as 1-13), topoisomerase (such as I, II, III),        Transcription factor, Transferase, Transferrin, Transforming        growth factor (TGF, such as beta) kinase, Transforming growth        factor TGF-β receptor kinase, Transglutaminase, Translocation        associated protein, Transmembrane glycoprotein NMB, Trop-2        calcium signal transducer, trophoblast glycoprotein (TPBG) gene,        Trophoblast glycoprotein, Tropomyosin receptor kinase (Trk)        receptor (such as TrkA, TrkB, TrkC), Tryptophan 5-hydroxylase,        Tubulin, Tumor necrosis factor (TNF, such as alpha, beta), Tumor        necrosis factor 13C receptor, tumor progression locus 2 (TPL2),        Tumor protein 53 (TP53) gene, Tumor suppressor candidate 2        (TUSC2) gene, Tumor specific neoantigens, Tyrosinase, Tyrosine        hydroxylase, tyrosine kinase (TK), Tyrosine kinase receptor,        Tyrosine kinase with immunoglobulin-like and EGF-like domains        (TIE) receptor, Tyrosine protein kinase ABL1 inhibitor,        Ubiquitin, Ubiquitin carboxyl hydrolase isozyme L5, Ubiquitin        thioesterase-14, Ubiquitin-conjugating enzyme E21 (UBE2I, UBC9),        Urease, Urokinase plasminogen activator, Uteroglobin, Vanilloid        VR1, Vascular cell adhesion protein 1, vascular endothelial        growth factor receptor (VEGFR), V-domain Ig suppressor of T-cell        activation (VISTA), VEGF-1 receptor, VEGF-2 receptor, VEGF-3        receptor, VEGF-A, VEGF-B, Vimentin, Vitamin D3 receptor,        Proto-oncogene tyrosine-protein kinase, Mer (Mer tyrosine kinase        receptor modulators), YAP (Yes-associated protein modulators),        Wee-1 protein kinase, Wilms' tumor antigen 1, Wilms' tumor        protein, WW domain containing transcription regulator protein 1        (TAZ), X-linked inhibitor of apoptosis protein, Zinc finger        protein transcription factor, or any combinations thereof.

Non-limiting examples of additional therapeutic agents may becategorized by their mechanism of action into, for example, thefollowing groups:

-   -   anti-metabolites/anti-cancer agents, such as pyrimidine analogs        floxuridine, capecitabine, cytarabine, CPX-351 (liposomal        cytarabine, daunorubicin), and TAS-118;    -   purine analogs, folate antagonists (such as pralatrexate), and        related inhibitors;    -   antiproliferative/antimitotic agents including natural products,        such as vinca alkaloids (vinblastine, vincristine) and        microtubule disruptors such as taxane (paclitaxel, docetaxel),        vinblastin, nocodazole, epothilones, vinorelbine (NAVELBINE®),        and epipodophyllotoxins (etoposide, teniposide);    -   DNA damaging agents, such as actinomycin, amsacrine, busulfan,        carboplatin, chlorambucil, cisplatin, cyclophosphamide        (CYTOXAN®), dactinomycin, daunorubicin, doxorubicin, epirubicin,        iphosphamide, melphalan, merchlorethamine, mitomycin C,        mitoxantrone, nitrosourea, procarbazine, taxol, Taxotere,        teniposide, etoposide, and triethylenethiophosphoramide;    -   DNA-hypomethylating agents, such as guadecitabine (SGI-110) and        ASTX727;    -   antibiotics such as dactinomycin, daunorubicin, doxorubicin,        idarubicin, anthracyclines, mitoxantrone, bleomycins, and        plicamycin (mithramycin);    -   enzymes such as L-asparaginase which systemically metabolizes        L-asparagine and deprives cells which do not have the capacity        to synthesize their own asparagine;    -   antiplatelet agents;    -   DNAi oligonucleotides targeting Bcl-2, such as PNT2258;    -   agents that activate or reactivate latent human immunodeficiency        virus (HIV), such as panobinostat and romidepsin;    -   asparaginase stimulators, such as crisantaspase (Erwinase®) and        GRASPA (ERY-001, ERY-ASP), and calaspargase pegol;    -   pan-Trk, ROS1 and ALK inhibitors, such as entrectinib and        TPX-0005;    -   anaplastic lymphoma kinase (ALK) inhibitors, such as alectinib        and ceritinib;    -   antiproliferative/antimitotic alkylating agents, such as        nitrogen mustard cyclophosphamide and analogs (melphalan,        chlorambucil, hexamethylmelamine, thiotepa), alkyl nitrosoureas        (carmustine) and analogs, streptozocin, and triazenes        (dacarbazine);    -   antiproliferative/antimitotic antimetabolites, such as folic        acid analogs (methotrexate);    -   platinum coordination complexes (cisplatin, oxiloplatinim, and        carboplatin), procarbazine, hydroxyurea, mitotane, and        aminoglutethimide;    -   hormones, hormone analogs (estrogen, tamoxifen, goserelin,        bicalutamide, and nilutamide), and aromatase inhibitors        (letrozole and anastrozole);    -   anticoagulants such as heparin, synthetic heparin salts, and        other inhibitors of thrombin;    -   fibrinolytic agents such as tissue plasminogen activator,        streptokinase, urokinase, aspirin, dipyridamole, ticlopidine,        and clopidogrel;    -   antimigratory agents;    -   antisecretory agents (breveldin);    -   immunosuppressives, such as tacrolimus, sirolimus, azathioprine,        and mycophenolate;    -   growth factor inhibitors, and vascular endothelial growth factor        inhibitors;    -   fibroblast growth factor inhibitors, such as FPA14;    -   anti-VEGFR antibodies, such as IMC-3C₅, GNR-011, LYN-00101, and        tanibirumab;    -   anti-VEGF/DDL4 antibodies, such as ABT-165;    -   anti-cadherins antibodies, such as HKT-288;    -   anti-CD70 antibodies, such as AMG-172;    -   anti-leucine-rich repeat containing 15 (LRRC15) antibodies, such        as ABBV-085 and ARGX-110;    -   angiotensin receptor blockers and nitric oxide donors;    -   antisense oligonucleotides, such as AEG35156, IONIS-KRAS-2.5Rx,        EZN-3042, RX-0201, IONIS-AR-2.5Rx, BP-100 (prexigebersen), and        IONIS-STAT3-2.5Rx;    -   DNA interference oligonucleotides, such as PNT2258 and AZD-9150;    -   anti-ANG-2 antibodies, such as MEDI3617, and LY3127804;    -   anti-ANG-1/ANG-2 antibodies, such as AMG-780;    -   anti-MET/EGFR antibodies, such as LY3164530;    -   anti-EGFR antibodies, such as ABT-414, AMG-595, necitumumab,        ABBV-221, depatuxizumab mafodotin (ABT-414), tomuzotuximab,        ABT-806, vectibix, modotuximab, and RM-1929;    -   anti-CSF1R antibodies, such as emactuzumab, LY3022855, AMG-820,        and FPA-008 (cabiralizumab);    -   anti-CD40 antibodies, such as RG7876, SEA-CD40, APX-005M, and        ABBV-428;    -   anti-endoglin antibodies, such as TRC105 (carotuximab);    -   anti-CD45 antibodies, such as 131I-BC8 (lomab-B);    -   anti-HER3 antibodies, such as LJM716, and GSK2849330;    -   anti-HER2 antibodies, such as margetuximab, MED14276, and        BAT-8001;    -   anti-HLA-DR antibodies, such as IMMU-114;    -   anti-IL-3 antibodies, such as JNJ-56022473;    -   anti-OX40 antibodies, such as MEDI6469, MEDI6383, MEDI0562        (tavolixizumab), MOXR0916, PF-04518600, RG-7888, GSK-3174998,        INCAGN1949, BMS-986178, GBR-8383, and ABBV-368;    -   anti-EphA3 antibodies, such as KB-004;    -   anti-CD20 antibodies, such as obinutuzumab, IGN-002;    -   anti-CD20/CD3 antibodies, such as RG7828;    -   anti-CD37 antibodies, such as AGS67E, and otlertuzumab        (TRU-016);    -   anti-ENPP3 antibodies, such as AGS-16C₃F;    -   anti-FGFR-3 antibodies, such as LY3076226, and B-701;    -   anti-FGFR-2 antibodies, such as GAL-F2;    -   anti-C₅ antibodies, such as ALXN-1210;    -   anti-CD27 antibodies, such as varlilumab (CDX-1127);    -   anti-TROP-2 antibodies, such as IMMU-132    -   anti-NKG2a antibodies, such as monalizumab;    -   anti-VISTA antibodies, such as HMBD-002;    -   anti-PVRIG antibodies, such as COM-701;    -   anti-EpCAM antibodies, such as VB4-845;    -   anti-BCMA antibodies, such as GSK-2857916    -   anti-CEA antibodies, such as RG-7813;    -   anti-cluster of differentiation 3 (CD3) antibodies, such as        MGD015;    -   anti-folate receptor alpha antibodies, such as IMGN853;    -   MCL-1 inhibitors, such as AMG-176, S-64315, AZD-5991, 483-LM,        A-1210477, UMI-77, and JKY-5-037;    -   epha2 inhibitors, such as MM-310;    -   anti LAG-3 antibodies, such as relatlimab (ONO-4482), LAG-525,        MK-4280, and REGN-3767, INCAGN2385;    -   raf kinase/VEGFR inhibitors, such as RAF-265;    -   polycomb protein (EED) inhibitors, such as MAK683;    -   anti-fibroblast activation protein (FAP)/IL-2R antibodies, such        as RG7461;    -   anti-fibroblast activation protein (FAP)/TRAIL-R² antibodies,        such as RG7386;    -   anti-fucosyl-GM1 antibodies, such as BMS-986012;    -   p38 MAP kinase inhibitors, such as ralimetinib;    -   PRMT1 inhibitors, such as MS203;    -   Sphingosine kinase 2 (SK2) inhibitors, such as opaganib;    -   FLT3-ITD inhibitors, such as BCI-332;    -   FLT3-ITD/Mer tyrosine kinase inhibitors, such as MRX-2843;    -   Nuclear erythroid 2-related factor 2 stimulators, such as        omaveloxolone (RTA-408);    -   Tropomyosin receptor kinase (TRK) inhibitors, such as LOXO-195,        and ONO-7579;    -   anti-ICOS antibodies, such as JTX-2011, and GSK3359609;    -   anti-DR5 (TRAIL2) antibodies, such as DS-8273, CTB-006,        INBRX-109, GEN-1029;    -   anti-Carcinoembryonic-antigen-related-cell-adhesion-molecule-6        (CEACAM6, CD66C) antibodies, such as BAY-1834942, NEO-201        (CEACAM 5/6);    -   anti-GD2 antibodies, such as APN-301;    -   anti-interleukin-17 (IL-17) antibodies, such as CJM-112;    -   anti-carbonic anhydrase IX antibodies, such as TX-250;    -   anti-CD38-attenukine, such as TAK573;    -   anti-Mucin 1 antibodies, such as gatipotuzumab;    -   anti-FTL3 antibodies, such as Flysyn, ASP-1235;    -   anti-FLT3/CD3 BiTE antibodies, such as AMG-427;    -   Mucin 1 inhibitors, such as GO-203-2C;    -   MARCKS protein inhibitors, such as BIO-11006;    -   Folate antagonists, such as arfolitixorin;    -   Galectin-3 inhibitors, such as GR-MD-02;    -   Phosphorylated P68 inhibitors, such as RX-5902;    -   CD95/TNF modulators, such as ofranergene obadenovec;    -   PI3K/Akt/mTOR inhibitors, such as ABTL-0812;    -   pan-PIM kinase inhibitors, such as INCB-053914;    -   PIM/FLT3 kinase inhibitors, such as MEN-1703 (SEL-24);    -   IL-12 gene stimulators, such as EGEN-001, and tavokinogene        telseplasmid;    -   Heat shock protein HSP90 inhibitors, such as TAS-116, and        PEN-866;    -   VEGF/HGF antagonists, such as MP-0250;    -   SYK tyrosine kinase/FLT3 tyrosine kinase inhibitors, such as        TAK-659 (mivavotinib);    -   SYK tyrosine kinase/JAK tyrosine kinase inhibitors, such as        ASN-002;    -   JAK3/JAK1/TBKI1 kinase inhibitors, such as CS-12912;    -   FLT3 tyrosine kinase inhibitor, such as FF-10101, HM-43239,        SKI-G-801;    -   FLT3 tyrosine kinase agonist, such as CDX-301;    -   EGFR/FLT3/ABL tyrosine kinase inhibitors, such as SKLB-1028;    -   FLT3/MEK1 inhibitors, such as E-6201;    -   IL-24 antagonist, such as AD-IL24;    -   NLRP3 (NACHT LRR PYD domain protein 3) modulators, such as        BMS-986299;    -   RIG-I agonists, such as RGT-100;    -   Aerolysin stimulators, such as topsalysin;    -   P-Glycoprotein 1 inhibitors, such as HM-30181A;    -   CSF-1 antagonists, such as ARRY-382, and BLZ-945;    -   CCR8 inhibitors, such as 1-309, SB-649701, HG-1013, RAP-310;    -   anti-Mesothelin antibodies, such as SEL-403;    -   Thymidine kinase stimulators, such as aglatimagene besadenovec;    -   Polo-like kinase 1 inhibitors, such as PCM-075;    -   TLR-7 agonists, such as TMX-101 (imiquimod);    -   NEDD8 inhibitors, such as pevonedistat (MLN-4924), and TAS-4464;    -   Pleiotropic pathway modulators, such as avadomide (CC-122);    -   FoxM1 inhibitors, such as thiostrepton;    -   Anti-MUC1 antibodies, such as Mab-AR-20.5;    -   anti-CD38 antibodies, such as isatuximab, and MOR-202;    -   UBA1 inhibitors, such as TAK-243;    -   Src tyrosine kinase inhibitors, such as VAL-201;    -   VDAC/HK inhibitors, such as VDA-1102;    -   BRAF/PI3K inhibitors, such as ASN-003;    -   Elf4a inhibitors, such as rohinitib, eFT226;    -   TP53 gene stimulators, such as ad-p53;    -   PD-L1/EGFR inhibitors, such as GNS-1480 (lazertinib);    -   PD-1/CTLA-4 inhibitors, such as PF-06936308;    -   Retinoic acid receptor alpha (RARα) inhibitors, such as SY-1425;    -   SIRT3 inhibitors, such as YC8-02;    -   Stromal cell-derived factor 1 ligand inhibitors, such as        olaptesed pegol (NOX-A12);    -   IL-4 receptor modulators, such as MDNA-55;    -   Arginase-I stimulators, such as pegzilarginase;    -   Topoisomerase I inhibitor/hypoxia inducible factor-1 alpha        inhibitors, such as PEG-SN38 (firtecan pegol);    -   Hypoxia inducible factor-1 alpha inhibitors, such as PT-2977,        and PT-2385;    -   CD122 agonists such as NKTR-214;    -   TLR7/TLR8 agonist, such as NKTR-262;    -   TLR7 agonists, such as DS-0509, GS-9620, LHC-165, TMX-101        (imiquimod);    -   p53 tumor suppressor protein stimulators such as kevetrin;    -   Mdm4/Mdm2 p53-binding protein inhibitors, such as ALRN-6924;    -   kinesin spindle protein (KSP) inhibitors, such as filanesib        (ARRY-520);    -   CD80-fc fusion protein inhibitors, such as FPT-155;    -   Menin and mixed lineage leukemia (MLL) inhibitors such as        KO-539;    -   Liver x receptor agonists, such as RGX-104;    -   IL-10 agonists, such as AM-0010;    -   EGFR/ErbB-2 inhibitors, such as varlitinib;    -   VEGFR/PDGFR inhibitors, such as vorolanib;    -   IRAK4 inhibitors, such as CA-4948;    -   anti-TLR-2 antibodies, such as OPN-305;    -   Calmodulin modulators, such as CBP-501;    -   Glucocorticoid receptor antagonists, such as relacorilant        (CORT-125134);    -   Second mitochondria-derived activator of caspases (SMAC) protein        inhibitors, such as BI-891065;    -   Lactoferrin modulators, such as LTX-315;    -   Kit tyrosine kinase/PDGF receptor alpha antagonists such as        DCC-2618;    -   KIT inhibitors, such as PLX-9486;    -   Exportin 1 inhibitors, such as eltanexor;    -   EGFR/ErbB2/Ephb4 inhibitors, such as tesevatinib;    -   anti-CD33 antibodies, such as IMGN-779;    -   anti-KMA antibodies, such as MDX-1097;    -   anti-TIM-3 antibodies, such as TSR-022, LY-3321367, and MBG-453;    -   anti-CD55 antibodies, such as PAT-SC1;    -   anti-PSMA antibodies, such as ATL-101;    -   anti-CD100 antibodies, such as VX-15;    -   anti-EPHA3 antibodies, such as fibatuzumab;    -   anti-Erbb antibodies, such as CDX-3379, HLX-02, and        seribantumab;    -   anti-APRIL antibodies, such as BION-1301;    -   Anti-Tigit antidbodies, such as BMS-986207, AGEN-1307, and        RG-6058;    -   anti-TIM-3 antibodies, such as INCAGN-2390;    -   CHST15 gene inhibitors, such as STNM-01;    -   RAS inhibitors, such as NEO-100;    -   Somatostatin receptor antagonist, such as OPS-201;    -   CEBPA gene stimulators, such as MTL-501;    -   DKK3 gene modulators, such as MTG-201;    -   Chemokine (CXCR1/CXCR2) inhibitors, such as SX-682;    -   p70s6k inhibitors, such as MSC2363318A;    -   methionine aminopeptidase 2 (MetAP2) inhibitors, such as M8891,        and APL-1202;    -   arginine N-methyltransferase 5 inhibitors, such as GSK-3326595;    -   anti-programmed cell death protein 1 (anti-PD-1) antibodies,        such as nivolumab (OPDIVO®, BMS-936558, MDX-1106), pembrolizumab        (KEYTRUDA®, MK-3477, SCH-900475, lambrolizumab, CAS Reg. No.        1374853-91-4), pidilizumab, PF-06801591, BGB-A317        (tislelizumab), GLS-010 (WBP-3055), AK-103 (HX-008), CS-1003,        HLX-10, MGA-012, BI-754091, REGN-2810 (cemiplimab), AGEN-2034,        JS-001 (toripalimab), JNJ-63723283, genolimzumab (CBT-501),        LZM-009, BCD-100, LY-3300054, SHR-1201, SHR-1210 (camrelizumab),        Sym-021, ABBV-181, AK-105, PD1-PIK, BAT-1306, BAT-1306, and        anti-programmed death-ligand 1 (anti-PD-L1) antibodies such as        BMS-936559, atezolizumab (MPDL3280A), durvalumab (MED14736),        avelumab, CK-301, (MSB0010718C), MEDI0680, CX-072, CBT-502,        PDR-001 (spartalizumab), TSR-042 (dostarlimab), MSB-2311,        JTX-4014, BGB-A333, SHR-1316, CS-1001 (WBP-3155, KN-035,        IBI-308, (sintilimab), HLX-20, KL-A167, STI-A1014, STI-A1015        (IMC-001), BCD-135, FAZ-053, TQB-2450, and MDX1105-01;    -   PD-L1/VISTA antagonists such as CA-170;    -   PD-1/PD-L1 inhibitors, such as INCB086550, GS-4224;    -   anti-PD-L1/TGFβ antibodies, such as M7824;    -   anti-transferrin antibodies, such as CX-2029;    -   anti-IL-8 (Interleukin-8) antibodies, such as HuMax-Inflam;    -   ATM (ataxia telangiectasia) inhibitors, such as AZD0156;    -   CHK1 inhibitors, such as GDC-0575, LY2606368 (prexasertib),        SRA737, and RG7741 (CHK1/2);    -   CXCR4 antagonists, such as BL-8040, LY2510924, burixafor        (TG-0054), X4P-002, and X4P-001-10;    -   EXH2 inhibitors, such as GSK2816126;    -   HER2 inhibitors, such as neratinib, and tucatinib (ONT-380);    -   KDM1 inhibitors, such as ORY-1001, IMG-7289, INCB-59872, and        GSK-2879552;    -   CXCR2 antagonists, such as AZD-5069;    -   GM-CSF antibodies, such as lenzilumab;    -   DNA dependent protein kinase inhibitors, such as MSC2490484A        (nedisertib), VX-984, and AsiDNA (DT-01);    -   protein kinase C (PKC) inhibitors, such as LXS-196, and        sotrastaurin;    -   Selective estrogen receptor downregulators (SERD), such as        fulvestrant (Faslodex®), RG6046, RG6047, elacestrant (RAD-1901)        and AZD9496;    -   Selective estrogen receptor covalent antagonists (SERCAs), such        as H3B-6545;    -   selective androgen receptor modulator (SARM), such as GTX-024,        and darolutamide;    -   transforming growth factor-beta (TGF-beta) kinase antagonists,        such as galunisertib;    -   anti-transforming growth factor-beta (TGF-beta) antibodies, such        as LY3022859, NIS793, and XOMA 089;    -   bispecific antibodies, such as MM-141 (IGF-1/ErbB3), MM-111        (Erb2/Erb3), JNJ-64052781 (CD19/CD3), PRS-343 (CD-137/HER2),        AFM26 (BCMA/CD16A), JNJ-61186372 (EGFR/cMET), AMG-211 (CEA/CD3),        RG7802 (CEA/CD3), ERY-974 (CD3/GPC3) vancizumab        (angiopoietins/VEGF), PF-06671008 (Cadherins/CD3), AFM-13        (CD16/CD30), APV0436 (CD123/CD3), flotetuzumab (CD123/CD3),        REGN-1979 (CD20/CD3), MCLA-117 (CD3/CLECI2A), MCLA-128        (HER2/HER3), JNJ-0819, JNJ-7564 (CD3/heme), AMG-757 (DLL3-CD3),        MGD-013 (PD-1/LAG-3), FS-118 (LAG-3/PD-L1) MGD-019        (PD-1/CTLA-4), KN-046 (PD-1/CTLA-4), MEDI-5752 (CTLA-4/PD-1),        RO-7121661 (PD-1/TIM-3), XmAb-20717 (PD-1/CTLA-4), AK-104        (CTLA-4/PD-1), AMG-330 (CD33/CD3), AMG-420 (BCMA/CD3), BI-836880        (VEFG/ANG2), JNJ-63709178 (CD123/CD3), MGD-007 (CD3/gpA33),        MGD-009 (CD3/B7H3), AGEN1223, IMCgp100 (CD3/gp100 T-cell        engager) and AGEN-1423, ATOR-1015 (CTLA-4/OX40), LY-3415244        (TIM3/PDL1), INHIBRX-105 (4-1BB/PDL1), faricimab (VEGF-A/ANG-2),        FAP-4-IBBL (4-1BB/FAP), XmAb-13676 (CD3/CD20), TG-1801        (CD19/CD47), XmAb-18087 (SSTR2/CD3), catumaxomab (CD3/EpCAM),        SAR-156597 (IL4/IL13), EMB-01 (EGFR/cMET), REGN-4018        (MUC16/CD3), RG-7828 (CD20/CD3), CC-93269 (CD3/BCMA), REGN-5458        (CD3/BCMA), navicixizumab (DLL4/VEGF), GRB-1302 (CD3/Erbb2),        vanucizumab (VEGF-A/ANG-2), GRB-1342 (CD38/CD3), GEM-333        (CD3/CD33), IMM-0306 (CD47/CD20);    -   Mutant selective EGFR inhibitors, such as PF-06747775, EGF816        (nazartinib), ASP8273, ACEA-0010, and BI-1482694;    -   Anti-GITR (glucocorticoid-induced tumor necrosis factor        receptor-related protein) antibodies, such as MED11873, FPA-154,        INCAGN-1876, TRX-518, BMS-986156, MK-1248, and GWN-323;    -   anti-delta-like protein ligand 3 (DDL3) antibodies, such as        rovalpituzumab tesirine;    -   anti-clusterin antibodies, such as AB-16B5;    -   anti-Ephrin-A4 (EFNA4) antibodies, such as PF-06647263;    -   anti-RANKL antibodies, such as denosumab;    -   anti-mesothelin antibodies, such as BMS-986148, and        Anti-MSLN-MMAE;    -   anti-sodium phosphate cotransporter 2B (NaP2B) antibodies, such        as lifastuzumab    -   anti-c-Met antibodies, such as ABBV-399;    -   Adenosine A2A receptor antagonists, such as CPI-444, AZD-4635,        preladenant, and PBF-509;    -   Alpha-ketoglutarate dehydrogenase (KGDH) inhibitors, such as        CPI-613;    -   XPO1 inhibitors, such as selinexor (KPT-330);    -   Isocitrate dehydrogenase 2 (IDH2) inhibitors, such as enasidenib        (AG-221);    -   IDH1 inhibitors such as AG-120, and AG-881 (IDH1 and IDH2),        IDH-305, and BAY-1436032;    -   interleukin-3 receptor (IL-3R) modulators, such as SL-401;    -   Arginine deiminase stimulators, such as pegargiminase        (ADI-PEG-20);    -   antibody-drug conjugates, such as MLN0264 (anti-GCC, guanylyl        cyclase C), T-DM1 (trastuzumab emtansine, Kadcycla, SYD985),        milatuzumab-doxorubicin (hCD74-DOX), brentuximab vedotin,        DCDT2980S, polatuzumab vedotin (RG-7596), SGN-CD70A, SGN-CD19A,        inotuzumab ozogamicin (CMC-544), lorvotuzumab mertansine,        SAR3419, isactuzumab govitecan, enfortumab vedotin (ASG-22ME),        ASG-15ME,    -   DS-8201 ((trastuzumab deruxtecan), 225Ac-lintuzumab, U3-1402,        177Lu-tetraxetan-tetuloma, tisotumab vedotin, anetumab        ravtansine, CX-2009, SAR-566658, W-0101, polatuzumab vedotin,        ABBV-085, gemtuzumab ozogamicin, ABT-414, glembatumumab vedotin        (CDX-011), labetuzumab govitecan (IMMU-130), sacituzumab        govitecan (IMMU-132), lifastuzumab vedotin, (RG-7599),        milatuzumab-doxorubicin (IMMU-110), indatuximab ravtansine        (BT-062), pinatuzumab vedotin (RG-7593), SGN-LIV1A, SGN-CD33A,        SAR566658, MLN2704, SAR408701, rovalpituzumab tesirine,        ABBV-399, AGS-16C₃F, ASG-22ME, AGS67E, AMG 172, AMG 595,        AGS-15E, BAY1129980, BAY1187982, BAY94-934 (anetumab        ravtansine), GSK2857916, Humax-TF-ADC (tisotumab vedotin),        IMGN289, IMGN529; IMGN853 (mirvetuximab soravtansine), LOP628,        PCA062, MDX-1203, MEDI-547, PF-06263507, PF-06647020,        PF-06647263, PF-06664178, RG7450, RG7458, RG7598, SAR566658,        SGN-CD33A;    -   claudin-18 inhibitors, such as claudiximab;    -   β-catenin inhibitors, such as CWP-291;    -   anti-CD73 antibodies, such as MEDI-9447 (oleclumab), CPX-006,        IPH-53, NZV-930, and BMS-986179;    -   CD73 antagonists, such as AB-680, PSB-12379, PSB-12441,        PSB-12425, and -708;    -   CD39/CD73 antagonists, such as PBF-1662;    -   chemokine receptor 2 (CCR) inhibitors, such as PF-04136309,        CCX-872, and BMS-813160 (CCR2/CCR5)    -   thymidylate synthase inhibitors, such as ONX-0801;    -   ALK/ROS1 inhibitors, such as lorlatinib;    -   tankyrase inhibitors, such as G007-LK;    -   Mdm2 p53-binding protein inhibitors, such as CMG-097, and        HDM-201;    -   c-PIM inhibitors, such as PIM447;    -   BRAF inhibitors, such as dabrafenib, vemurafenib, encorafenib        (LGX818), and PLX8394;    -   sphingosine kinase-2 (SK2) inhibitors, such as Yeliva®        (ABC294640);    -   cell cycle inhibitors, such as selumetinib (MEK1/2), and        sapacitabine;    -   AKT inhibitors such as MK-2206, ipatasertib, afuresertib,        AZD5363, ARQ-092, capivasertib, and triciribine;    -   anti-CTLA-4 (cytotoxic T-lymphocyte protein-4) antibodies, such        as tremelimumab, ipilimumab (BMS-734016), AGEN-1884, BMS-986218,        AGEN1181, BMS-986249, MK-1308, REGN-4659, ADU-1604, CS-1002,        BCD-145, APL-509, JS-007, BA-3071, ONC-392, AGEN-2041, JHL-1155,        KN-044, CG-0161, ATOR-1144, PBI-5D3H5, BA-3071;    -   CTLA-4 (cytotoxic T-lymphocyte protein-4) inhibitors, such as        BPI-002;    -   TLR-3 agonist/interferon inducers, such as Poly-ICLC        (NSC-301463)    -   c-MET inhibitors, such as AMG-337, savolitinib, tivantinib        (ARQ-197), capmatinib, and tepotinib, ABT-700, AG213, AMG-208,        JNJ-38877618 (OMO-1), merestinib, and HQP-8361;    -   c-Met/VEGFR inhibitors, such as BMS-817378, and TAS-115;    -   c-Met/RON inhibitors, such as BMS-777607;    -   c-Met/VEGF2/AXL/RON/Mer/FLT3 inhibitors, such as CT-053        (ningetinib);    -   c-Kit/VEGFR2/PDGFR/VEGFR3/FLT1/FLT3 inhibitors, such as SHR-1020        (famitinib L-malate);    -   BRAF/EGFR inhibitors, such as BGB-283;    -   bcr/abl inhibitors, such as rebastinib, and asciminib;    -   MNK1/MNK2 inhibitors, such as eFT-508;    -   mTOR inhibitor/cytochrome P450 3A4 stimulators, such as TYME-88    -   lysine-specific demethylase-1 (LSD1) inhibitors, such as        CC-90011;    -   Pan-RAF inhibitors, such as LY3009120, LXH254, and TAK-580;    -   Raf/MEK inhibitors, such as RG7304;    -   CSF1R/KIT and FLT3 inhibitors, such as pexidartinib (PLX3397);    -   kinase inhibitors, such as vandetanib;    -   E selectin antagonists, such as GMI-1271;    -   differentiation inducers, such as tretinoin;    -   epidermal growth factor receptor (EGFR) inhibitors, such as        osimertinib (AZD-9291);    -   topoisomerase inhibitors, such as doxorubicin, daunorubicin,        dactinomycin, eniposide, epirubicin, etoposide, idarubicin,        irinotecan, mitoxantrone, pixantrone, sobuzoxane, topotecan,        irinotecan, MM-398 (liposomal irinotecan), vosaroxin and        GPX-150, aldoxorubicin, AR-67, mavelertinib, AST-2818, avitinib        (ACEA-0010), and irofulven (MGI-114);    -   corticosteroids, such as cortisone, dexamethasone,        hydrocortisone, methylprednisolone, prednisone, and        prednisolone;    -   growth factor signal transduction kinase inhibitors;    -   nucleoside analogs, such as DFP-10917;    -   Axl inhibitors, such as BGB-324 (bemcentinib), and SLC-0211;    -   BET inhibitors, such as INCB-054329, INCB057643, TEN-010,        AZD-5153, ABT-767, BMS-986158, CC-90010, GSK525762 (molibresib),        NHWD-870, ODM-207, GSK-2820151, GSK-121015A, ZBC246, ZBC260,        ZEN3694, FT-1101, RG-6146, CC-90010, mivebresib, BI-894999,        PLX-2853, PLX-51107, CPI-0610, and GS-5829;    -   PARP inhibitors, such as olaparib, rucaparib, veliparib,        talazoparib, ABT-767, and BGB-290, fluzolepali (SHR-3162),        niraparib (JNJ-64091742), bendamustine hydrochloride;    -   IMP-4297, SC-10914, IDX-1197, HWH-340, CK-102, simmiparib;    -   PARP/Tankyrase inhibitors such as 2X-121 (e-7499)    -   Proteasome inhibitors, such as ixazomib, carfilzomib        (Kyprolis®), and marizomi;    -   Glutaminase inhibitors, such as CB-839 (telaglenastat);    -   Vaccines, such as peptide vaccine TG-01 (RAS), GALE-301,        GALE-302, nelipepimut-s, SurVaxM, DSP-7888, TPIV-200, PVX-410,        VXL-100, DPX-E7, ISA-101, 6MHP, OSE-2101, galinpepimut-S,        SVN53-67/M57-KLH, IMU-131; bacterial vector vaccines such as        CR5-207/GVAX, axalimogene filolisbac (ADXS11-001); adenovirus        vector vaccines such as nadofaragene firadenovec; autologous        Gp96 vaccine; dendritic cells vaccines, such as CVactm,        stapuldencel-T, eltrapuldencel-T, SL-701, BSK01TM,        rocapuldencel-T (AGS-003), DCVAC, CVac™, stapuldencel-T,        eltrapuldencel-T, SL-701, BSK01™, ADXS31-142; oncolytic vaccines        such as, talimogene laherparepvec, pexastimogene devacirepvec,        GL-ONC1, MG1-MA3, parvovirus H-1, ProstAtak, enadenotucirev,        MG1MA3, ASN-002 (TG-1042); therapeutic vaccines, such as        CVAC-301, CMP-001, PF-06753512, VBI-1901, TG-4010, ProscaVax™;        tumor cell vaccines, such as Vigil® (IND-14205), Oncoquest-L        vaccine; live attenuated, recombinant, serotype 1 poliovirus        vaccine, such as PVS-RIPO; Adagloxad simolenin; MEDI-0457;        DPV-001 a tumor-derived, autophagosome enriched cancer vaccine;        RNA vaccines such as, CV-9209, LV-305; DNA vaccines, such as        MEDI-0457, MVI-816, INO-5401; modified vaccinia virus Ankara        vaccine expressing p53, such as MVA-p53; DPX-Survivac; BriaVax™;        GI-6301; GI-6207; and GI-4000;    -   10-103; Neoantigen peptide vaccines, such as AGEN-2017, GEN-010,        NeoVax, RG-6180, GEN-009, PGV-001 (TLR-3 agonist), GRANITE-001,        NEO-PV-01; Peptide vaccines that target heat shock proteins,        such as PhosphoSynVax™; Vitespen (HSPPC-96-C);    -   anti-DLL4 (delta like ligand 4) antibodies, such as demcizumab;    -   STAT-3 inhibitors, such as napabucasin (BBI-608);    -   ATPase p97 inhibitors, such as CB-5083;    -   smoothened (SMO) receptor inhibitors, such as Odomzo®        (sonidegib, formerly LDE-225), LEQ506, vismodegib (GDC-0449),        BMS-833923, glasdegib (PF-04449913), LY2940680, and        itraconazole;    -   interferon alpha ligand modulators, such as interferon alpha-2b,        interferon alpha-2a biosimilar (Biogenomics), ropeginterferon        alfa-2b (AOP-2014, P-1101, PEG IFN alpha-2b), Multiferon        (Alfanative, Viragen), interferon alpha 1b, Roferon-A (Canferon,        Ro-25-3036), interferon alfa-2a follow-on biologic        (Biosidus)(Inmutag, Inter 2A), interferon alfa-2b follow-on        biologic (Biosidus-Bioferon, Citopheron, Ganapar, Beijing Kawin        Technology—Kaferon), Alfaferone, pegylated interferon alpha-1b,        peginterferon alfa-2b follow-on biologic (Amega), recombinant        human interferon alpha-1b, recombinant human interferon        alpha-2a, recombinant human interferon alpha-2b, veltuzumab-IFN        alpha 2b conjugate, Dynavax (SD-101), and interferon alfa-n1        (Humoferon, SM-10500, Sumiferon);    -   interferon gamma ligand modulators, such as interferon gamma        (OH-6000, Ogamma 100);    -   IL-6 receptor modulators, such as tocilizumab, siltuximab, and        AS-101 (CB-06-02, IVX-Q-101);    -   Telomerase modulators, such as, tertomotide (GV-1001, HR-2802,        Riavax) and imetelstat (GRN-163, JNJ-63935937);    -   DNA methyltransferases inhibitors, such as temozolomide        (CCRG-81045), decitabine, guadecitabine (S-110, SGI-110),        KRX-0402, RX-3117, RRx-001, and azacitidine;    -   DNA gyrase inhibitors, such as pixantrone and sobuzoxane;    -   Bcl-2 family protein inhibitors, such as ABT-263, venetoclax        (ABT-199), ABT-737, and AT-101;    -   Notch inhibitors, such as LY3039478 (crenigacestat), tarextumab        (anti-Notch2/3), and BMS-906024;    -   anti-myostatin inhibitors, such as landogrozumab;    -   hyaluronidase stimulators, such as PEGPH-20;    -   Wnt pathway inhibitors, such as SM-04755, PRI-724, and WNT-974;    -   gamma-secretase inhibitors, such as PF-03084014, MK-0752, and        RO-4929097;    -   Grb-2 (growth factor receptor bound protein-2) inhibitors, such        as BPT001;    -   TRAIL pathway-inducing compounds, such as ONC201, and ABBV-621;    -   Focal adhesion kinase inhibitors, such as VS-4718, defactinib,        and GSK2256098;    -   hedgehog inhibitors, such as saridegib, sonidegib (LDE225),        glasdegib and vismodegib;    -   Aurora kinase inhibitors, such as alisertib (MLN-8237), and        AZD-2811, AMG-900, barasertib, and ENMD-2076;    -   HSPB1 modulators (heat shock protein 27, HSP27), such as        brivudine, and apatorsen;    -   ATR inhibitors, such as BAY-937, AZD6738, AZD6783, VX-803,        VX-970 (berzosertib) and VX-970;    -   mTOR inhibitors, such as sapanisertib and vistusertib (AZD2014),        and ME-344;    -   mTOR/PI3K inhibitors, such as gedatolisib, GSK2141795,        omipalisib, and RG6114;    -   Hsp90 inhibitors, such as AUY922, onalespib (AT13387), SNX-2112,        and SNX5422;    -   Murine double minute (mdm2) oncogene inhibitors, such as        DS-3032b, RG7775, AMG-232, HDM201, and idasanutlin (RG7388);    -   CD137 agonists, such as urelumab, (PF-05082566), AGEN2373,        ADG-106, and utomilumab (PF-05082566);    -   STING agonists, such as ADU-S100 (MIW-815), SB-11285, MK-1454,        SR-8291, AdVCA0848, GSK-532, SYN-STING, MSA-1, and SR-8291;    -   FGFR inhibitors, such as FGF-401, INCB-054828, BAY-1163877,        AZD4547, JNJ-42756493, LY2874455, and Debio-1347;    -   fatty acid synthase (FASN) inhibitors, such as TVB-2640;    -   Anti-KIR monoclonal antibodies, such as lirilumab (IPH-2102),        and IPH-4102;    -   Antigen CD19 inhibitors, such as MOR208, MEDI-551, AFM-11, and        inebilizumab;    -   CD44 binders, such as A6;    -   protein phosphatease 2A (PP2A) inhibitors, such as LB-100;    -   CYP17 inhibitors, such as seviteronel (VT-464), ASN-001,        ODM-204, CFG920, and abiraterone acetate;    -   RXR agonists, such as IRX4204;    -   hedgehog/smoothened (hh/Smo) antagonists, such as taladegib, and        patidegib;    -   complement C₃ modulators, such as Imprime PGG;    -   IL-15 agonists, such as ALT-803, NKTR-255, and hetIL-15;    -   EZH2 (enhancer of zeste homolog 2) inhibitors, such as        tazemetostat, CPI-1205, and GSK-2816126;    -   Oncolytic viruses, such as pelareorep, CG-0070, MV-NIS therapy,        HSV-1716, DS-1647, VCN-01, ONCOS-102, TBI-1401, tasadenoturev        (DNX-2401), vocimagene amiretrorepvec, RP-1, CVA21, Celyvir,        LOAd-703, and OBP-301;    -   DOT1L (histone methyltransferase) inhibitors, such as        pinometostat (EPZ-5676);    -   toxins such as Cholera toxin, ricin, Pseudomonas exotoxin,        Bordetella pertussis adenylate cyclase toxin, diphtheria toxin,        and caspase activators;    -   DNA plasmids, such as BC-819    -   PLK inhibitors of PLK 1, 2, and 3, such as volasertib (PLK1);    -   WEEl inhibitors, such as AZD1775 (adavosertib);    -   Rho kinase (ROCK) inhibitors, such as AT13148, and KD025;    -   ERK inhibitors, such as GDC-0994, LY3214996, and MK-8353;    -   IAP inhibitors, such as ASTX660, debio-1143, birinapant,        APG-1387, and LCL-161;    -   RNA polymerase inhibitors, such as lurbinectedin (PM-1183), and        CX-5461;    -   Tubulin inhibitors, such as PM-184, BAL-101553 (lisavanbulin),        OXI-4503, fluorapacin (AC-0001), and plinabulin;    -   Toll-like receptor 4 (TL4) agonists, such as G100, GSK1795091,        and PEPA-10;    -   Elongation factor 1 alpha 2 inhibitors, such as plitidepsin;    -   CD95 inhibitors, such as APG-101, APO-010, and asunercept;    -   WT1 inhibitors, such as DSP-7888;    -   splicing factor 3B subunit1 (SF3B1) inhibitors, such as H3B-8800    -   PDGFR alpha/KIT mutant-specific inhibitors such as BLU-285;    -   SHP-2 inhibitors, such as TNO155 (SHP-099), and RMC-4550;    -   Microbiome modulators, such as SER-401, EDP-1503, MRx-0518; and    -   retinoid Z receptor gamma (RORy) agonists, such as LYC-55716;

In some embodiments, provided herein are methods of treating orpreventing a cancer or hyper-proliferative disease in a human or animalhaving or at risk of having the cancer or hyper-proliferative disease isprovided, comprising administering to the human or animal atherapeutically effective amount of a compound of Formula I, I-Z, I-E,II-Z, IIa-Z, IIb-Z, III-Z, or IIIa-Z as disclosed herein, or apharmaceutically acceptable salt thereof, in combination with atherapeutically effective amount of one or more (e.g., one, two, three,one or two, or one to three) additional therapeutic agents selected fromthe group consisting of apoptosis signal-regulating kinase (ASK)inhibitors; Bruton's tyrosine kinase (BTK) inhibitors; cluster ofdifferentiation 47 (CD47) inhibitors; cyclin-dependent kinase (CDK)inhibitors; discoidin domain receptor (DDR) inhibitors; histonedeacetylase (HDAC) inhibitors; indoleamine-pyrrole-2,3-dioxygenase(IDO1) inhibitors; Janus kinase (JAK) inhibitors; lysyl oxidase-likeprotein (LOXL) inhibitors; matrix metalloprotease (MMP) inhibitors;mitogen-activated protein kinase (MEK) inhibitors; phosphatidylinositol3-kinase (PI3K) inhibitors; spleen tyrosine kinase (SYK) inhibitors;toll-like receptor 8 (TLR8) inhibitors; toll-like receptor 9 (TLR9)inhibitors; tyrosine-kinase inhibitors (TKIs), or a pharmaceuticallyacceptable salt of any of the foregoing, or any combinations thereof.Non-limiting examples include:

-   -   MCL-1 inhibitors, such as AMG-176, AMG-397, S-64315, and        AZD-5991, 483-LM, A-1210477, UMI-77, JKY-5-037; Examples of MCL1        inhibitors include, but are not limited to, those described in        WO-2018183418, WO-2016033486, and WO-2017147410;    -   SHP-2 inhibitors, such as TNO155 (SHP-099), RMC-4550, JAB-3068,        RMC-4630; Examples of SHP2 inhibitors include, but are not        limited to, those described in WO-2018172984 and WO-2017211303;    -   Hematopoietic Progenitor Kinase 1 (HPK1) inhibitors; Examples of        Hematopoietic Progenitor Kinase 1 (HPK1) inhibitors include, but        are not limited to, those described in WO-2018183956,        WO-2018183964, WO-2018167147, WO-2018183964, WO-2016205942,        WO-2018049214, WO-2018049200, WO-2018049191, WO-2018102366,        WO-2018049152 and WO-2016090300;    -   Apoptosis Signal-Regulating Kinase (ASK) Inhibitors: ASK        inhibitors include ASKI inhibitors. Examples of ASKI inhibitors        include, but are not limited to, those described in WO        2011/008709 (Gilead Sciences) and WO 2013/112741 (Gilead        Sciences);    -   Bruton's Tyrosine Kinase (BTK) Inhibitors: Examples of BTK        inhibitors include, but are not limited to,        (S)-6-amino-9-(1-(but-2-ynoyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one,        acalabrutinib (ACP-196), BGB-3111, CB988, HM71224, ibrutinib,        M-2951 (evobrutinib), M7583, tirabrutinib (ONO-4059), PRN-1008,        spebrutinib (CC-292), TAK-020, vecabrutinib, ARQ-531, SHR-1459,        DTRMWXHS-12, and TAS-5315;    -   Cluster ofDifferentiation 47 (CD47) inhibitors: Examples of CD47        inhibitors include, but are not limited to anti-CD47 mAbs        (Vx-1004), anti-human CD47 mAbs (CNTO-7108), CC-90002,        CC-90002-ST-001, humanized anti-CD47 antibody (Hu5F9-G4),        NI-1701, NI-1801, RCT-1938, and TTI-621;    -   Cyclin-dependent Kinase (CDK) Inhibitors: CDK inhibitors include        inhibitors of CDK 1, 2, 3, 4, 6, 7 and 9, such as abemaciclib,        alvocidib (HMR-1275, flavopiridol), AT-7519, dinaciclib,        ibrance, FLX-925, LEE001, palbociclib, ribociclib, rigosertib,        selinexor, UCN-01, SY1365, CT-7001, SY-1365, G1T38, milciclib,        trilaciclib, and TG-02;    -   Discoidin Domain Receptor (DDR) Inhibitors: DDR inhibitors        include inhibitors of DDR1 and/or DDR2. Examples of DDR        inhibitors include, but are not limited to, those disclosed in        WO 2014/047624 (Gilead Sciences), US 2009-0142345 (Takeda        Pharmaceutical), US 2011-0287011 (Oncomed Pharmaceuticals), WO        2013/027802 (Chugai Pharmaceutical), and WO 2013/034933        (Imperial Innovations);    -   Histone Deacetylase (HDAC) Inhibitors: Examples of HDAC        inhibitors include, but are not limited to, abexinostat,        ACY-241, AR-42, BEBT-908, belinostat, CKD-581, CS-055        (HBI-8000), CUDC-907 (fimepinostat), entinostat, givinostat,        mocetinostat, panobinostat, pracinostat, quisinostat        (JNJ-26481585), resminostat, ricolinostat, SHP-141, valproic        acid (VAL-001), vorinostat, tinostamustine, remetinostat, and        entinostat;    -   Indoleamine-pyrrole-2,3-dioxygenase (IDO) inhibitors: Examples        of IDO1 inhibitors include, but are not limited to, BLV-0801,        epacadostat, F-001287, GBV-1012, GBV-1028, GDC-0919, indoximod,        NKTR-218, NLG-919-based vaccine, PF-06840003,        pyranonaphthoquinone derivatives (SN-35837), resminostat,        SBLK-200802, BMS-986205, and shIDO-ST, EOS-200271, KHK-2455, and        LY-3381916;    -   Janus Kinase (JAK) Inhibitors: JAK inhibitors inhibit JAK1,        JAK2, and/or JAK3. Examples of JAK inhibitors include, but are        not limited to, AT9283, AZD1480, baricitinib, BMS-911543,        fedratinib, filgotinib (GLPG0634), gandotinib (LY2784544),        INCB039110 (itacitinib), lestaurtinib, momelotinib (CYT0387),        NS-018, pacritinib (SB1518), peficitinib (ASP015K), ruxolitinib,        tofacitinib (formerly tasocitinib), INCB052793, and XL019;    -   Lysyl Oxidase-Like Protein (LOXL) Inhibitors: LOXL inhibitors        include inhibitors of LOXL1, LOXL2, LOXL3, LOXL4, and/or LOXL5.        Examples of LOXL inhibitors include, but are not limited to, the        antibodies described in WO 2009/017833 (Arresto Biosciences).        Examples of LOXL2 inhibitors include, but are not limited to,        the antibodies described in WO 2009/017833 (Arresto        Biosciences), WO 2009/035791 (Arresto Biosciences), and WO        2011/097513 (Gilead Biologics);    -   Matrix Metalloprotease (MVIP) Inhibitors: MMP inhibitors include        inhibitors of MMP1 through 10. Examples of MMP9 inhibitors        include, but are not limited to, marimastat (BB-2516),        cipemastat (Ro 32-3555), GS-5745 (andecaliximab) and those        described in WO 2012/027721 (Gilead Biologics);    -   Mitogen-activated Protein Kinase (MEK) Inhibitors: MEK        inhibitors include antroquinonol, binimetinib, cobimetinib        (GDC-0973, XL-518), MT-144, selumetinib (AZD6244), sorafenib,        trametinib (GSK1120212), uprosertib+trametinib, PD-0325901,        pimasertib, LTT462, AS703988, CC-90003, and refametinib;    -   Phosphatidylinositol 3-kinase (PI3K) Inhibitors: PI3K inhibitors        include inhibitors of PI3Kγ, PI3K6, PI3KO, PI3Ka, and/or        pan-PI3K. Examples of PI3K inhibitors include, but are not        limited to, ACP-319, AEZA-129, AMG-319, AS252424, AZD8186, BAY        10824391, BEZ235, buparlisib (BKM120), BYL719 (alpelisib),        CH5132799, copanlisib (BAY 80-6946), duvelisib, GDC-0032,        GDC-0077, GDC-0941, GDC-0980, GSK2636771, GSK2269557, idelalisib        (Zydelig®), INCB50465, IPI-145, IPI-443, IPI-549, KAR4141,        LY294002, LY3023414, MLN1117, OXY1IA, PA799, PX-866, RG7604,        rigosertib, RP5090, RP6530, SRX3177, taselisib, TG100115,        TGR-1202 (umbralisib), TGX221, WX-037, X-339, X-414, XL147        (SAR245408), XL499, XL756, wortmannin, ZSTK474, and the        compounds described in WO 2005/113556 (ICOS), WO 2013/052699        (Gilead Calistoga), WO 2013/116562 (Gilead Calistoga), WO        2014/100765 (Gilead Calistoga), WO 2014/100767 (Gilead        Calistoga), and WO 2014/201409 (Gilead Sciences);    -   Spleen Tyrosine Kinase (SYK) Inhibitors: Examples of SYK        inhibitors include, but are not limited to,        6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine,        BAY-61-3606, cerdulatinib (PRT-062607), entospletinib,        fostamatinib (R⁷⁸⁸), HMPL-523, NVP-QAB 205 AA, R¹¹², R³⁴³,        tamatinib (R⁴⁰⁶), GS-9876, and those described in U.S. Pat. No.        8,450,321 (Gilead Connecticut) and those described in U.S.        2015/0175616;    -   Toll-like receptor 8 (TLR8) inhibitors: Examples of TLR8        inhibitors include, but are not limited to, E-6887, IMO-4200,        IMO-8400, IMO-9200, MCT-465, MEDI-9197, motolimod, resiquimod,        GS-9688, VTX-1463, and VTX-763;    -   Toll-like receptor 9 (TLR9) inhibitors: Examples of TLR9        inhibitors include, but are not limited to, AST-008, IMO-2055,        IMO-2125, lefitolimod, litenimod, MGN-1601, and PUL-042; and    -   Tyrosine-kinase Inhibitors (TKIs): TKIs may target epidermal        growth factor receptors (EGFRs) and receptors for fibroblast        growth factor (FGF), platelet-derived growth factor (PDGF), and        vascular endothelial growth factor (VEGF). Examples of TKIs        include, but are not limited to, afatinib, ARQ-087        (derazantinib), asp5878, AZD3759, AZD4547, bosutinib,        brigatinib, cabozantinib, cediranib, crenolanib, dacomitinib,        dasatinib, dovitinib, E-6201, erdafitinib, erlotinib, gefitinib,        gilteritinib (ASP-2215), FP-1039, HM61713, icotinib, imatinib,        KX2-391 (Src), lapatinib, lestaurtinib, lenvatinib, midostaurin,        nintedanib, ODM-203, osimertinib (AZD-9291), ponatinib,        poziotinib, quizartinib, radotinib, rociletinib, sulfatinib        (HMPL-012), sunitinib, famitinib L-malate, (MAC-4), tivoanib,        TH-4000, and MEDI-575 (anti-PDGFR antibody).

As used herein, the term “chemotherapeutic agent” or “chemotherapeutic”(or “chemotherapy” in the case of treatment with a chemotherapeuticagent) is meant to encompass any non-proteinaceous (i.e., non-peptidic)chemical compound useful in the treatment of cancer. Examples ofchemotherapeutic agents include but are not limited to:

-   -   alkylating agents such as thiotepa and cyclophosphamide        (CYTOXAN®); alkyl sulfonates such as busulfan, improsulfan, and        piposulfan; aziridines such as benzodepa, carboquone,        meturedepa, and uredepa; ethylenimines and methylamelamines        including altretamine, triethylenemelamine,        triethylenephosphoramide, triethylenethiophosphoramide, and        trimemylolomelamine; acetogenins, especially bullatacin and        bullatacinone; a camptothecin, including synthetic analog        topotecan; bryostatin, callystatin; CC-1065, including its        adozelesin, carzelesin, and bizelesin synthetic analogs;        cryptophycins, particularly cryptophycin 1 and cryptophycin 8;        dolastatin; duocarmycin, including the synthetic analogs KW-2189        and CBI-TMI; eleutherobin; 5-azacytidine; pancratistatin; a        sarcodictyin; spongistatin; nitrogen mustards such as        chlorambucil, chlornaphazine, cyclophosphamide, glufosfamide,        evofosfamide, bendamustine, estramustine, ifosfamide,        mechlorethamine, mechlorethamine oxide hydrochloride, melphalan,        novembichin, phenesterine, prednimustine, trofosfamide, and        uracil mustard; nitrosoureas such as carmustine, chlorozotocin,        foremustine, lomustine, nimustine, and ranimustine; antibiotics        such as the enediyne antibiotics (e.g., calicheamicin,        especially calicheamicin gammaII and calicheamicin phiIl),        dynemicin including dynemicin A, bisphosphonates such as        clodronate, an esperamicin, neocarzinostatin chromophore and        related chromoprotein enediyne antibiotic chromomophores,        aclacinomycins, actinomycin, authramycin, azaserine, bleomycins,        cactinomycin, carabicin, carrninomycin, carzinophilin,        chromomycins, dactinomycin, daunorubicin, detorubicin,        6-diazo-5-oxo-L-norleucine, doxorubicin (including        morpholino-doxorubicin, cyanomorpholino-doxorubicin,        2-pyrrolino-doxorubicin, and deoxydoxorubicin), epirubicin,        esorubicin, idarubicin, marcellomycin, mitomycins such as        mitomycin C, mycophenolic acid, nogalamycin, olivomycins,        peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin,        streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin,        and zorubicin; anti-metabolites such as methotrexate and        5-fluorouracil (5-FU); folic acid analogs such as demopterin,        methotrexate, pteropterin, and trimetrexate; purine analogs such        as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine;        pyrimidine analogs such as ancitabine, azacitidine,        6-azauridine, carmofur, cytarabine, dideoxyuridine,        doxifluridine, enocitabine, and floxuridine; androgens such as        calusterone, dromostanolone propionate, epitiostanol,        mepitiostane, and testolactone; anti-adrenals such as        aminoglutethimide, mitotane, and trilostane; folic acid        replinishers such as frolinic acid; radiotherapeutic agents such        as Radium-223; trichothecenes, especially T-2 toxin, verracurin        A, roridin A, and anguidine; taxoids such as paclitaxel        (TAXOL®), abraxane, docetaxel (TAXOTERE®), cabazitaxel,        BIND-014, tesetaxel; platinum analogs such as cisplatin and        carboplatin, NC-6004 nanoplatin; aceglatone; aldophosphamide        glycoside; aminolevulinic acid; eniluracil; amsacrine;        hestrabucil; bisantrene; edatraxate; defofamine; demecolcine;        diaziquone; elformthine; elliptinium acetate; an epothilone;        etoglucid; gallium nitrate; hydroxyurea; lentinan; leucovorin;        lonidamine; maytansinoids such as maytansine and ansamitocins;        mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin;        phenamet; pirarubicin; losoxantrone; fluoropyrimidine; folinic        acid; podophyllinic acid; 2-ethylhydrazide; procarbazine;        polysaccharide-K (PSK); razoxane; rhizoxin; sizofiran;        spirogermanium; tenuazonic acid; trabectedin, triaziquone;        2,2′,2″-tricUorotriemylamine; urethane; vindesine; dacarbazine;        mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine;        arabinoside (“Ara-C”); cyclophosphamide; thiopeta; chlorambucil;        gemcitabine (GEMZAR®); 6-thioguanine; mercaptopurine;        methotrexate; vinblastine; platinum; etoposide (VP-16);        ifosfamide; mitroxantrone; vancristine; vinorelbine        (NAVELBINE®); novantrone; teniposide; edatrexate; daunomycin;        aminopterin; xeoloda; ibandronate; CPT-11; topoisomerase        inhibitor RFS 2000; difluoromethylomithine (DFMO); retinoids        such as retinoic acid; capecitabine; NUC-1031; FOLFIRI        (fluorouracil, leucovorin, and irinotecan); and pharmaceutically        acceptable salts, acids, or derivatives of any of the above.

Also included in the definition of “chemotherapeutic agent” areanti-hormonal agents such as anti-estrogens and selective estrogenreceptor modulators (SERMs), inhibitors of the enzyme aromatase,anti-androgens, and pharmaceutically acceptable salts, acids orderivatives of any of the above that act to regulate or inhibit hormoneaction on tumors.

Anti-Hormonal Agents

Examples of anti-estrogens and SERMs include, for example, tamoxifen(including NOLVADEX™), raloxifene, droloxifene, 4-hydroxytamoxifen,trioxifene, keoxifene, LY117018, onapristone, and toremifene(FARESTON®).

Inhibitors of the enzyme aromatase regulate estrogen production in theadrenal glands. Examples include 4(5)-imidazoles, aminoglutethimide,megestrol acetate (MEGACE®), exemestane, formestane, fadrozole, vorozole(RIVISOR®), letrozole (FEMARA®), and anastrozole (ARIMIDEX®).

Examples of anti-androgens include apalutamide, abiraterone,enzalutamide, flutamide, galeterone, nilutamide, bicalutamide,leuprolide, goserelin, ODM-201, APC-100, and ODM-204.

Examples of progesterone receptor antagonist include onapristone.

Anti-Angiogenic Agents

Anti-angiogenic agents include, but are not limited to, retinoid acidand derivatives thereof, 2-methoxyestradiol, ANGIOSTATIN®, ENDOSTATIN®,regorafenib, necuparanib, suramin, squalamine, tissue inhibitor ofmetalloproteinase-1, tissue inhibitor of metalloproteinase-2,plasminogen activator inhibitor-1, plasminogen activator inhibitor-2,cartilage-derived inhibitor, paclitaxel (nab-paclitaxel), plateletfactor 4, protamine sulphate (clupeine), sulphated chitin derivatives(prepared from queen crab shells), sulphated polysaccharidepeptidoglycan complex (sp-pg), staurosporine, modulators of matrixmetabolism including proline analogs such as 1-azetidine-2-carboxylicacid (LACA), cishydroxyproline, d,I-3,4-dehydroproline, thiaproline,α,α′-dipyridyl, beta-aminopropionitrile fumarate,4-propyl-5-(4-pyridinyl)-2(3h)-oxazolone, methotrexate, mitoxantrone,heparin, interferons, 2 macroglobulin-serum, chicken inhibitor ofmetalloproteinase-3 (ChIMP-3), chymostatin, beta-cyclodextrintetradecasulfate, eponemycin, fumagillin, gold sodium thiomalate,d-penicillamine, beta-1-anticollagenase-serum, alpha-2-antiplasmin,bisantrene, lobenzarit disodium, n-2-carboxyphenyl-4-chloroanthronilicacid disodium or “CCA”, thalidomide, angiostatic steroid, carboxyaminoimidazole, metalloproteinase inhibitors such as BB-94, andinhibitors of S100A9 such as tasquinimod. Other anti-angiogenesis agentsinclude antibodies, preferably monoclonal antibodies against theseangiogenic growth factors: beta-FGF, alpha-FGF, FGF-5, VEGF isoforms,VEGF-C, HGF/SF, and Ang-1/Ang-2.

Anti-Fibrotic Agents

Anti-fibrotic agents include, but are not limited to, the compounds suchas beta-aminoproprionitrile (BAPN), as well as the compounds disclosedin U.S. Pat. No. 4,965,288 relating to inhibitors of lysyl oxidase andtheir use in the treatment of diseases and conditions associated withthe abnormal deposition of collagen and U.S. Pat. No. 4,997,854 relatingto compounds which inhibit LOX for the treatment of various pathologicalfibrotic states, which are herein incorporated by reference. Furtherexemplary inhibitors are described in U.S. Pat. No. 4,943,593 relatingto compounds such as 2-isobutyl-3-fluoro-, chloro-, or bromo-allylamine,U.S. Pat. Nos. 5,021,456, 5,059,714, 5,120,764, 5,182,297, 5,252,608relating to 2-(1-naphthyloxymemyl)-3-fluoroallylamine, and US2004-0248871, which are herein incorporated by reference.

Exemplary anti-fibrotic agents also include the primary amines reactingwith the carbonyl group of the active site of the lysyl oxidases, andmore particularly those which produce, after binding with the carbonyl,a product stabilized by resonance, such as the following primary amines:emylenemamine, hydrazine, phenylhydrazine, and their derivatives;semicarbazide and urea derivatives; aminonitriles such as BAPN or2-nitroethylamine; unsaturated or saturated haloamines such as2-bromo-ethylamine, 2-chloroethylamine, 2-trifluoroethylamine,3-bromopropylamine, and p-halobenzylamines; and selenohomocysteinelactone.

Other anti-fibrotic agents are copper chelating agents penetrating ornot penetrating the cells. Exemplary compounds include indirectinhibitors which block the aldehyde derivatives originating from theoxidative deamination of the lysyl and hydroxylysyl residues by thelysyl oxidases. Examples include the thiolamines, particularlyD-penicillamine, and its analogs such as2-amino-5-mercapto-5-methylhexanoic acid,D-2-amino-3-methyl-3-((2-acetamidoethyl)dithio)butanoic acid,p-2-amino-3-methyl-3-((2-aminoethyl)dithio)butanoic acid,sodium-4-((p-1-dimethyl-2-amino-2-carboxyethyl)dithio)butane sulphurate,2-acetamidoethyl-2-acetamidoethanethiol sulphanate, andsodium-4-mercaptobutanesulphinate trihydrate.

Immunotherapeutic Agents

Examples of immunotherapeutic agents include but are not limited totherapeutic antibodies suitable for treating patients. Some examples oftherapeutic antibodies include abagovomab, ABP-980, adecatumumab,afutuzumab, alemtuzumab, altumomab, amatuximab, anatumomab, arcitumomab,bavituximab, bectumomab, bevacizumab, bivatuzumab, blinatumomab,brentuximab, cantuzumab, catumaxomab, CC49, cetuximab, citatuzumab,cixutumumab, clivatuzumab, conatumumab, dacetuzumab, dalotuzumab,daratumumab, detumomab, dinutuximab, drozitumab, duligotumab,dusigitumab, ecromeximab, elotuzumab, emibetuzumab, ensituximab,ertumaxomab, etaracizumab, farletuzumab, ficlatuzumab, figitumumab,flanvotumab, futuximab, ganitumab, gemtuzumab, girentuximab,glembatumumab, ibritumomab, igovomab, imgatuzumab, indatuximab,inotuzumab, intetumumab, ipilimumab (YERVOY®, MDX-010, BMS-734016, andMDX-101), iratumumab, labetuzumab, lexatumumab, lintuzumab,lorvotuzumab, lucatumumab, mapatumumab, matuzumab, milatuzumab,minretumomab, mitumomab, mogamulizumab, moxetumomab, naptumomab,narnatumab, necitumumab, nimotuzumab, nofetumomab, OBI-833,obinutuzumab, ocaratuzumab, ofatumumab, olaratumab, onartuzumab,oportuzumab, oregovomab, panitumumab, parsatuzumab, pasudotox,patritumab, pemtumomab, pertuzumab, pintumomab, pritumumab, racotumomab,radretumab, ramucirumab (Cyramza®), rilotumumab, rituximab, robatumumab,samalizumab, satumomab, sibrotuzumab, siltuximab, solitomab, simtuzumab,tacatuzumab, taplitumomab, tenatumomab, teprotumumab, tigatuzumab,tositumomab, trastuzumab, tucotuzumab, ublituximab, veltuzumab,vorsetuzumab, votumumab, zalutumumab, and 3F8. Rituximab can be used fortreating indolent B-cell cancers, including marginal-zone lymphoma, WM,CLL and small lymphocytic lymphoma. In some embodiments, a combinationof Rituximab and chemotherapy agents is especially effective.

The exemplified therapeutic antibodies may be further labeled orcombined with a radioisotope particle such as indium-111, yttrium-90(90Y-clivatuzumab), or iodine-131.

Cancer Gene Therapy and Cell Therapy

Cancer gene therapy and cell therapy include the insertion of a normalgene into cancer cells to replace a mutated or altered gene; geneticmodification to silence a mutated gene; genetic approaches to directlykill the cancer cells; including the infusion of immune cells designedto replace most of the patient's own immune system to enhance the immuneresponse to cancer cells, or activate the patient's own immune system (Tcells or Natural Killer cells) to kill cancer cells, or find and killthe cancer cells; and genetic approaches to modify cellular activity tofurther alter endogenous immune responsiveness against cancer.

Gene Editors

Examples of genome editing system include a CRISPR/Cas9 system, a zincfinger nuclease system, a TALEN system, a homing endonucleases system,and a meganuclease system.

CAR-T Cell Therapy and TCR-T Cell Therapy

CAR-T cell therapy includes a population of immune effector cellsengineered to express a chimeric antigen receptor (CAR), wherein the CARcomprises a tumor antigen-binding domain. The immune effector cell is aT cell or an NK cell. TCR-T cell therapy includes TCR-T cells that areengineered to target tumor derived peptides present on the surface oftumor cells. Cells can be autologous or allogeneic.

In some embodiments, the CAR comprises an antigen binding domain, atransmembrane domain, and an intracellular signaling domain.

In some embodiments, the intracellular domain comprises a primarysignaling domain, a costimulatory domain, or both of a primary signalingdomain and a costimulatory domain.

In some embodiments, the primary signaling domain comprises a functionalsignaling domain of one or more proteins selected from the groupconsisting of CD3 zeta, CD3 gamma, CD3 delta, CD3 epsilon, common FcRgamma (FCERIG), FcR beta (Fc Epsilon Rlb), CD79a, CD79b, Fcgamma RIIa,DAP10, and DAP12.

In some embodiments, the costimulatory domain comprises a functionaldomain of one or more proteins selected from the group consisting ofCD27, CD28, 4-1BB (CD137), OX40, CD30, CD40, PD-1, ICOS, lymphocytefunction-associated antigen-1 (LFA-I), CD2, CD7, LIGHT, NKG2C, B7-H3, aligand that specifically binds with CD83, CDS, ICAM-1, GITR, BAFFR, HVEM(LIGHTR), SLAMF7, NKp80 (KLRFI), CD160, CD19, CD4, CD8alpha, CD8beta,IL2R beta, IL2R gamma, IL7R alpha, ITGA4, VLA1, CD49a, ITGA4, IA4,CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD 1 ld, ITGAE, CD103, ITGAL, CD 1la, LFA-1, ITGAM, CD1 lb, ITGAX, CD1 lc, ITGB1, CD29, ITGB2, CD18,LFA-1, ITGB7, TNFR2, TRANCE/RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4),CD84, CD96 (Tactile), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1,CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Ly108), SLAM (SLAMFI, CD150,IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, LAT, GADS, SLP-76,PAG/Cbp, NKp44, NKp30, NKp46, and NKG2D.

In some embodiments, the transmembrane domain comprises a transmembranedomain of a protein selected from the group consisting of the alpha,beta or zeta chain of the T-cell receptor, CD28, CD3 epsilon, CD45, CD4,CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137,CD154, KIRDS2, OX40, CD2, CD27, LFA-1 (CD1 la, CD18), ICOS (CD278),4-1BB (CD137), GITR, CD40, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRF1),CD160, CD19, IL2R beta, IL2R gamma, IL7R u, ITGAI, VLA1, CD49a, ITGA4,IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD1 ild, ITGAE, CD103, ITGAL,CD1 la, LFA-1, ITGAM, CD1 lb, ITGAX, CD1 lc, ITGB1, CD29, ITGB2, CD18,LFA-1, ITGB7, TNFR2, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96(Tactile), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100(SEMA4D), SLAMF6 (NTB-A, Ly108), SLAM (SLAMFI, CD150, IPO-3), BLAME(SLAMF8), SELPLG (CD162), LTBR, PAG/Cbp, NKp44, NKp30, NKp46, NKG2D, andNKG2C.

In some embodiments, the antigen binding domain binds a tumor antigen.

In some embodiments, the tumor antigen is selected from the groupconsisting of: CD19; CD123; CD22; CD30; CD171; CS-1 (also referred to asCD2 subset 1, CRACC, SLAMF7, CD319, and 19A24); C-type lectin-likemolecule-1 (CLL-1 or CLECLI); CD33; epidermal growth factor receptorvariant III (EGFRvlll); ganglioside G2 (GD2); ganglioside GD3(aNeuSAc(2-8)aNeuSAc(2-3)bDGaip(1-4)bDGIcp(1-1)Cer); TNF receptor familymember B cell maturation (BCMA); Tn antigen ((Tn Ag) or(GaNAcu-Ser/Thr)); prostate-specific membrane antigen (PSMA); Receptortyrosine kinase-like orphan receptor 1 (RORI); Fms-Like, Tyrosine Kinase3 (FLT3); Tumor-associated glycoprotein 72 (TAG72); CD38; CD44v6;Carcinoembryonic antigen (CEA); Epithelial cell adhesion molecule(EPCAM); B7H3 (CD276); KIT (CD117); Interleukin-13 receptor subunitalpha-2 (IL-13Ra2 or CD213A2); Mesothelin; Interleukin 11 receptor alpha(IL-11Ra); prostate stem cell antigen (PSCA); Protease Serine 21(Testisin or PRSS21); vascular endothelial growth factor receptor 2(VEGFR2); Lewis(Y) antigen; CD24; Platelet-derived growth factorreceptor beta (PDGFR-beta); Stage-specificembryonic antigen-4 (SSEA-4);CD20; delta like 3 (DLL3); Folate receptor alpha; Receptortyrosine-protein kinase, ERBB2 (Her2/neu); Mucin 1, cell surfaceassociated (MUC1); epidermal growth factor receptor (EGFR); neural celladhesion molecule (NCAM); Prostase; prostatic acid phosphatase (PAP);elongation factor 2 mutated (ELF2M); Ephrin B2; fibroblast activationprotein alpha (FAP); insulin-like growth factor 1 receptor (IGF-Ireceptor), carbonic anhydrase IX (CAIX); Proteasome (Prosome, Macropain)Subunit, Beta Type, 9 (LMP2); glycoprotein 100 (gp100); oncogene fusionprotein consisting of breakpoint cluster region (BCR) and Abelsonmurineleukemia viral oncogene homolog 1 (Abl) (bcr-abl); tyrosinase;ephrin type-A receptor 2 (EphA2); Fucosyl GM1; sialyl Lewis adhesionmolecule (sLe); ganglioside GM3 (aNeuSAc(2-3)bDGalp(1-4)bDGlcp(1-1)Cer);transglutaminase 5 (TGS5); high molecularweight-melanomaassociatedantigen (HMWMAA); o-acetyl-GD2 ganglioside(OAcGD2); Folate receptor beta; tumor endothelial marker 1 (TEM1/CD248);tumor endothelial marker 7-related (TEM7R); six transmembrane epithelialantigen of the prostate I (STEAP1); claudin 6 (CLDN6); thyroidstimulating hormone receptor (TSHR); G protein-coupled receptor class Cgroup 5, member D (GPRCSD); chromosome X open reading frame 61(CXORF61); CD97; CD179a; anaplastic lymphoma kinase (ALK); Polysialicacid; placenta-specific 1 (PLAC1); hexasaccharide portion of globoHglycoceramide (GoboH); mammary gland differentiation antigen (NY-BR-1);uroplakin 2 (UPK2); Hepatitis A virus cellular receptor 1 (HAVCR1);adrenoceptor beta 3 (ADRB3); pannexin 3 (PANX3); G protein-coupledreceptor 20 (GPR20); lymphocyte antigen 6 complex, locus K 9 (LY6K);Olfactory receptor 51E2 (ORS IE2); TCR Gamma Alternate Reading FrameProtein (TARP); Wilms tumor protein (WTi); Cancer/testis antigen 1(NY-ESO-1); Cancer/testis antigen 2 (LAGE-1a); Melanomaassociatedantigen 1 (MAGE-A1); ETS translocation-variant gene 6, located onchromosome 12p (ETV6-AML); sperm protein 17 (SPA17); X Antigen Family,Member 1A (XAGE1); angiopoietin-binding cell surface receptor 2 (Tie 2);melanoma cancer testis antigen-1 (MADCT-1); melanoma cancer testisantigen-2 (MAD-CT-2); Fos-related antigen 1; tumor protein p53, (p53);p53 mutant; prostein; survivin; telomerase; prostate carcinoma tumorantigen-1 (PCTA-1 or Galectin 8), melanoma antigen recognized by T cells1 (MelanA or MARTI); Rat sarcoma (Ras) mutant; human Telomerase reversetranscriptase (hTERT); sarcoma translocation breakpoints; melanomainhibitor of apoptosis (ML-IAP); ERG (transmembrane protease, serine 2(TMPRSS2) ETS fusion gene); N-Acetyl glucosaminyl-transferase V (NA17);paired box protein Pax-3 (PAX3); Androgen receptor; Cyclin B1; v-mycavian myelocytomatosis viral oncogene neuroblastoma derived homolog(MYCN); Ras Homolog Family Member C (RhoC); Tyrosinase-related protein 2(TRP-2); Cytochrome P450 1B1 (CYP IBI); CCCTC-Binding Factor (ZincFinger Protein)-Like (BORIS or Brother of the Regulator of ImprintedSites), Squamous Cell Carcinoma Antigen Recognized By T Cells 3 (SART3);Paired box protein Pax-5 (PAX5); proacrosin binding protein sp32 (OY-TESI); lymphocyte-specific protein tyrosine kinase (LCK); A kinase anchorprotein 4 (AKAP-4); synovial sarcoma, X breakpoint 2 (SSX2); Receptorfor Advanced Glycation Endproducts (RAGE-I); renal ubiquitous 1 (RUI);renal ubiquitous 2 (RU2); legumain; human papilloma virus E6 (HPV E6);human papilloma virus E7 (HPV E7); intestinal carboxyl esterase; heatshock protein 70-2 mutated (mut hsp70-2); CD79a; CD79b; CD72;Leukocyte-associated immunoglobulin-like receptor 1 (LAIRI); Fc fragmentof IgA receptor (FCAR or CD89); Leukocyte immunoglobulin-like receptorsubfamily A member 2 (LILRA2); CD300 molecule-like family member f(CD300LF); C-type lectin domain family 12 member A (CLEC12A); bonemarrow stromal cell antigen 2 (BST2); EGF-like modulecontainingmucin-like hormone receptor-like 2 (EMR2); lymphocyte antigen 75 (LY75);Glypican-3 (GPC3); Fc receptor-like 5 (FCRL5); and immunoglobulinlambda-like polypeptide 1 (IGLL1).

In some embodiments, the tumor antigen is selected from CD150, 5T4,ActRIIA, B7, BMCA, CA-125, CCNA1, CD123, CD126, CD138, CD14, CD148,CD15, CD19, CD20, CD200, CD21, CD22, CD23, CD24, CD25, CD26, CD261,CD262, CD30, CD33, CD362, CD37, CD38, CD4, CD40, CD40L, CD44, CD46, CD5,CD52, CD53, CD54, CD56, CD66a-d, CD74, CD8, CD80, CD92, CE7, CS-1,CSPG4, ED-B fibronectin, EGFR, EGFRvIII, EGP-2, EGP-4, EPHa2, ErbB2,ErbB3, ErbB4, FBP, GD2, GD3, HER1-HER2 in combination, HER2-HER3 incombination, HERV-K, HIV-1 envelope glycoprotein gp120, HIV-1 envelopeglycoprotein gp41, HLA-DR, HM1.24, HMW-MAA, Her2, Her2/neu, IGF-1R,IL-IIRalpha, IL-13R-alpha2, IL-2, IL-22R-alpha, IL-6, IL-6R, Ia, Ii,L1-CAM, L1-cell adhesion molecule, Lewis Y, L1-CAM, MAGE A3, MAGE-A1,MART-1, MUC1, NKG2C ligands, NKG2D Ligands, NYESO-1, OEPHa2, PIGF, PSCA,PSMA, ROR1, T101, TAC, TAG72, TIM-3, TRAIL-R¹, TRAIL-R¹ (DR4), TRAIL-R²(DR5), VEGF, VEGFR2, WT-I, a G-protein coupled receptor,alphafetoprotein (AFP), an angiogenesis factor, an exogenous cognatebinding molecule (ExoCBM), oncogene product, anti-folate receptor,c-Met, carcinoembryonic antigen (CEA), cyclin (D 1), ephrinB2,epithelial tumor antigen, estrogen receptor, fetal acethycholine ereceptor, folate binding protein, gp100, hepatitis B surface antigen,kappa chain, kappa light chain, kdr, lambda chain, livin,melanoma-associated antigen, mesothelin, mouse double minute 2 homolog(MDM2), mucin 16 (MUC16), mutated p53, mutated ras, necrosis antigens,oncofetal antigen, ROR2, progesterone receptor, prostate specificantigen, tEGFR, tenascin, P2-Microgiobuiin, and Fc Receptor-like 5(FcRL5).

Non limiting examples of cell therapies include Algenpantucel-L,Sipuleucel-T, (BPX-501) rivogenlecleucel U.S. Pat. No. 9,089,520,WO2016100236, AU-105, ACTR-087, activated allogeneic natural killercells CNDO-109-AANK, MG-4101, AU-101, BPX-601, FATE-NK100, LFU-835hematopoietic stem cells, Imilecleucel-T, baltaleucel-T, PNK-007,UCARTCS1, ET-1504, ET-1501, ET-1502, ET-190, CD19-ARTEMIS, ProHema,FT-1050-treated bone marrow stem cell therapy, CD4CARNK-92 cells,CryoStim, AlloStim, lentiviral transduced huCART-meso cells, CART-22cells, EGFRt/19-28z/4-1BBL CART cells, autologous 4H11-28z/fIL-12/EFGRtT cell, CCR5-SBC-728-HSPC, CAR4-1BBZ, CH-296, dnTGFbRII-NY-ESOc259T,Ad-RTS-IL-12, IMA-101, IMA-201, CARMA-0508, TT-18, CMD-501, CMD-503,CMD-504, CMD-502, CMD-601, CMD-602, and CSG-005.

In some embodiments, the tumor targeting antigen includes:Alpha-fetoprotein, such as ET-1402, and AFP-TCR; Anthrax toxin receptor1, such as anti-TEM8 CAR T-cell therapy; B cell maturation antigens(BCMA), such as bb-2121, UCART-BCMA, ET-140, KITE-585, MCM-998,LCAR-B38M, CART-BCMA, SEA-BCMA, BB212, UCART-BCMA, ET-140, P-BCMA-101,and AUTO-2 (APRIL-CAR; Anti-CLL-1 antibodies, such as KITE-796;Anti-PD-L1-CAR tank cell therapy, such as KD-045; B7 homolog 6, such asCAR-NKp30 and CAR-B7H6; B-lymphocyte antigen CD19, such as TBI-1501,CTL-119 huCART-19 T cells, JCAR-015 U.S. Pat. No. 7,446,190, JCAR-014,JCAR-017, (WO2016196388, WO2016033570, W2015157386), axicabtageneciloleucel (KTE-C₁₉), U.S. Pat. Nos. 7,741,465, 6,319,494, UCART-19,EBV-CTL, T tisagenlecleucel-T (CTL019), W2012079000, WO2017049166,CD19CAR-CD28-CD3zeta-EGFRt-expressing T cells, CD19/4-1BBL armored CAR Tcell therapy, C-CAR-011, CIK-CAR.CD19, CDi9CAR-28-zeta T cells,PCAR-019, MatchCART, DSCAR-01, and IM19 CAR-T; B-lymphocyte antigenCD20, such as ACTR707; B-lymphocyte antigen CD19/B-lymphocyte antigen22, such as TC-310; B-lymphocyte cell antigen 22, such as UCART-22, andJCAR-018 (WO2016090190); NY-ESO-1, such as GSK-3377794, and TBI-1301;Carbonic anhydrase, such as DC-Ad-GMCAIX; Caspase 9 suicide gene, suchas CaspaCIDe DLI, and BPX-501; CCR5, such as SB-728; CDw123, such asMB-102, and UCART-123; CD20m such as CBM-C20.1; CD4, such as ICG-122;CD30, such as CART30 (CBM-C30.1; CD33, such as CIK-CAR.CD33; CD38, suchas T-007, and UCART-38; CD40 ligand, such as BPX-201; CEACAM protein 4modulators, such as MG7-CART; Claudin 6, such as CSG-002; EBV targeted,such as CMD-003; MUC16, such as autologous 4H11-28z/fnL-12/EFGRt T cell;Endonuclease, such as PGN-201; Epstein-Barr virus specificT-lymphocytes, such as TT-10; Erbb2, such as CST-102 and CIDeCAR;Ganglioside (GD2), such as 4SCAR-GD2; folate hydrolase 1 (FOLH1,Glutamate carboxypeptidase II, PSMA) such as CIK-CAR.PSMA,CART-PSMA-TGFßRDN, and P-PSMA-101; Glypican-3 (GPC3), such as TT-16 andGLYCAR; Hepatocyte growth factor receptor, such as anti-cMet RNA CAR T;Human papillomavirus E7 protein, such as KITE-439; Immunoglobulin gammaFc receptor III, such as ACTR087; IL-12, such as DC-RTS-IL-12; IL-12agonist/mucin 16, such as JCAR-020; IL-13 alpha 2, such as MB-101; IL-2,such as CST-101; K-Ras GTPase, such as anti-KRAS G12V mTCR cell therapy;Neural cell adhesion molecule L1 LlCAM (CD171), such as JCAR-023; Latentmembrane protein 1/Latent membrane protein 2, such asAd5f35-LMPd-2-transduced autologous dendritic cells; Melanoma associatedantigen 10, such as MAGE-A10C₇₉₆T and MAGE-A10 TCR; Melanoma associatedantigen 3/Melanoma associated antigen 6 (MAGE A3/A6) such as KITE-718;Mesothelin, such as CSG-MESO and TC-210; NKG2D, such as NKR-2; Ntrkr1tyrosine kinase receptor, such as JCAR-024; PRAM, such as BPX-701 andIMCgp100; T-lymphocyte, such as TT-12; Tumor infiltrating lymphocytes,such as LN-144 and LN-145; and Wilms tumor protein, such as JTCR-016,WT1-CTL.

Lymphoma or Leukemia Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating lymphoma or leukemia. These agents include aldesleukin,alvocidib, amifostine trihydrate, aminocamptothecin, antineoplaston A10,antineoplaston AS2-1, anti-thymocyte globulin, arsenic trioxide, Bcl-2family protein inhibitor ABT-263, beta alethine, BMS-345541, bortezomib(VELCADE®), bortezomib (VELCADE®, PS-341), bryostatin 1, bulsulfan,campath-1H, carboplatin, carfilzomib (Kyprolis®), carmustine,caspofungin acetate, CC-5103, chlorambucil, CHOP (cyclophosphamide,doxorubicin, vincristine, and prednisone), cisplatin, cladribine,clofarabine, curcumin, CVP (cyclophosphamide, vincristine, andprednisone), cyclophosphamide, cyclosporine, cytarabine, denileukindiftitox, dexamethasone, docetaxel, dolastatin 10, doxorubicin,doxorubicin hydrochloride, DT-PACE (dexamethasone, thalidomide,cisplatin, doxorubicin, cyclophosphamide, and etoposide), enzastaurin,epoetin alfa, etoposide, everolimus (RAD001), FCM (fludarabine,cyclophosphamide, and mitoxantrone), FCR (fludarabine, cyclophosphamide,and rituximab), fenretinide, filgrastim, flavopiridol, fludarabine, FR(fludarabine and rituximab), geldanamycin (17-AAG), hyperCVAD(hyperfractionated cyclophosphamide, vincristine, doxorubicin,dexamethasone, methotrexate, and cytarabine), ICE (iphosphamide,carboplatin, and etoposide), ifosfamide, irinotecan hydrochloride,interferon alpha-2b, ixabepilone, lenalidomide (REVLIMID®, CC-5013),lymphokine-activated killer cells, MCP (mitoxantrone, chlorambucil, andprednisolone), melphalan, mesna, methotrexate, mitoxantronehydrochloride, motexafin gadolinium, mycophenolate mofetil, nelarabine,obatoclax (GX15-070), oblimersen, octreotide acetate, omega-3 fattyacids, Omr-IgG-am (WNIG, Omrix), oxaliplatin, paclitaxel, palbociclib(PD0332991), pegfilgrastim, PEGylated liposomal doxorubicinhydrochloride, perifosin, prednisolone, prednisone, recombinant flt3ligand, recombinant human thrombopoietin, recombinant interferon alfa,recombinant interleukin-11, recombinant interleukin-12, rituximab,R-CHOP (rituximab and CHOP), R-CVP (rituximab and CVP), R-FCM (rituximaband FCM), R-ICE (rituximab and ICE), and R-MCP (rituximab and MCP),R-roscovitine (seliciclib, CYC202), sargramostim, sildenafil citrate,simvastatin, sirolimus, styryl sulphones, tacrolimus, tanespimycin,temsirolimus (CCl-779), thalidomide, therapeutic allogeneic lymphocytes,thiotepa, tipifarnib, vincristine, vincristine sulfate, vinorelbineditartrate, SAHA (suberanilohydroxamic acid, or suberoyl, anilide, andhydroxamic acid), vemurafenib (Zelboraf®), and venetoclax (ABT-199).

One modified approach is radioimmunotherapy, wherein a monoclonalantibody is combined with a radioisotope particle, such as indium-111,yttrium-90, and iodine-131. Examples of combination therapies include,but are not limited to, iodine-131 tositumomab (BEXXAR®), yttrium-90ibritumomab tiuxetan (ZEVALIN®), and BEXXAR® with CHOP.

The above-mentioned therapies can be supplemented or combined with stemcell transplantation or treatment. Therapeutic procedures includeperipheral blood stem cell transplantation, autologous hematopoieticstem cell transplantation, autologous bone marrow transplantation,antibody therapy, biological therapy, enzyme inhibitor therapy, totalbody irradiation, infusion of stem cells, bone marrow ablation with stemcell support, in vitro-treated peripheral blood stem celltransplantation, umbilical cord blood transplantation, immunoenzymetechnique, low-LET cobalt-60 gamma ray therapy, bleomycin, conventionalsurgery, radiation therapy, and non-myeloablative allogeneichematopoietic stem cell transplantation.

Non-Hodgkin's Lymphomas Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating non-Hodgkin's lymphomas (NHL), especially those of B cellorigin, which include monoclonal antibodies, standard chemotherapyapproaches (e.g., CHOP, CVP, FCM, MCP, and the like),radioimmunotherapy, and combinations thereof, especially integration ofan antibody therapy with chemotherapy.

Examples of unconjugated monoclonal antibodies for the treatment ofNHL/B-cell cancers include rituximab, alemtuzumab, human or humanizedanti-CD20 antibodies, lumiliximab, anti-TNF-related apoptosis-inducingligand (anti-TRAIL), bevacizumab, galiximab, epratuzumab, SGN-40, andanti-CD74.

Examples of experimental antibody agents used in treatment of NHL/B-cellcancers include ofatumumab, ha20, PRO131921, alemtuzumab, galiximab,SGN-40, CHIR-12.12, epratuzumab, lumiliximab, apolizumab, milatuzumab,and bevacizumab.

Examples of standard regimens of chemotherapy for NHL/B-cell cancersinclude CHOP, FCM, CVP, MCP, R-CHOP, R-FCM, R-CVP, and R-MCP.

Examples of radioimmunotherapy for NHL/B-cell cancers include yttrium-90ibritumomab tiuxetan (ZEVALIN®) and iodine-131 tositumomab (BEXXAR®).

Mantle Cell Lymphoma Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating mantle cell lymphoma (MCL), which include combinationchemotherapies such as CHOP, hyperCVAD, and FCM. These regimens can alsobe supplemented with the monoclonal antibody rituximab to formcombination therapies R-CHOP, hyperCVAD-R, and R-FCM. Any of theabove-mentioned therapies may be combined with stem cell transplantationor ICE in order to treat MCL.

Other examples of therapeutic agents suitable for treating MCL include:

-   -   immunotherapy, such as monoclonal antibodies (like rituximab)        and cancer vaccines, such as GTOP-99, which are based on the        genetic makeup of an individual patient's tumor;    -   radioimmunotherapy, wherein a monoclonal antibody is combined        with a radioisotope particle, such as iodine-131 tositumomab        (BEXXAR®), yttrium-90 ibritumomab tiuxetan (ZEVALIN), and        BEXXAR® in sequential treatment with CHOP;    -   autologous stem cell transplantation coupled with high-dose        chemotherapy, administering proteasome inhibitors such as        bortezomib (VELCADE® or PS-341), or administering        antiangiogenesis agents such as thalidomide, especially in        combination with rituximab;    -   drugs that lead to the degradation of Bcl-2 protein and increase        cancer cell sensitivity to chemotherapy, such as oblimersen, in        combination with other chemotherapeutic agents;    -   mTOR inhibitors, which can lead to inhibition of cell growth and        even cell death. Non-limiting examples are sirolimus,        temsirolimus (TORISEL®, CCI-779), CC-115, CC-223, SF-1126,        PQR-309 (bimiralisib), voxtalisib, GSK-2126458, and temsirolimus        in combination with RITUXAN®, VELCADE®, or other        chemotherapeutic agents;    -   other agents such as flavopiridol, palbociclib (PD0332991),        R-roscovitine (selicicilib, CYC202), styryl sulphones, obatoclax        (GX15-070), TRAIL, Anti-TRAIL death receptors DR4 and DR5        antibodies, temsirolimus (TORISEL®, CC-779), everolimus        (RAD001), BMS-345541, curcumin, SAHA, thalidomide, lenalidomide        (REVLIMID®, CC-5013), and geldanamycin (17-AAG).

Waldenstrom's Macroglobulinemia Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating Waldenstrom's Macroglobulinemia (WM), which includealdesleukin, alemtuzumab, alvocidib, amifostine trihydrate,aminocamptothecin, antineoplaston A10, antineoplaston AS2-1,anti-thymocyte globulin, arsenic trioxide, autologous humantumor-derived HSPPC-96, Bcl-2 family protein inhibitor ABT-263, betaalethine, bortezomib (VELCADE®), bryostatin 1, busulfan, campath-1H,carboplatin, carmustine, caspofungin acetate, CC-5103, cisplatin,clofarabine, cyclophosphamide, cyclosporine, cytarabine, denileukindiftitox, dexamethasone, docetaxel, dolastatin 10, doxorubicinhydrochloride, DT-PACE, enzastaurin, epoetin alfa, epratuzumab(hLL2-anti-CD22 humanized antibody), etoposide, everolimus, fenretinide,filgrastim, fludarabine, ifosfamide, indium-111 monoclonal antibodyMN-14, iodine-131 tositumomab, irinotecan hydrochloride, ixabepilone,lymphokine-activated killer cells, melphalan, mesna, methotrexate,mitoxantrone hydrochloride, monoclonal antibody CD19 (such astisagenlecleucel-T, CART-19, CTL-019), monoclonal antibody CD20,motexafin gadolinium, mycophenolate mofetil, nelarabine, oblimersen,octreotide acetate, omega-3 fatty acids, oxaliplatin, paclitaxel,pegfilgrastim, PEGylated liposomal doxorubicin hydrochloride,pentostatin, perifosine, prednisone, recombinant ft3 ligand, recombinanthuman thrombopoietin, recombinant interferon alfa, recombinantinterleukin-11, recombinant interleukin-12, rituximab, sargramostim,sildenafil citrate (VIAGRA®), simvastatin, sirolimus, tacrolimus,tanespimycin, thalidomide, therapeutic allogeneic lymphocytes, thiotepa,tipifamib, tositumomab, veltuzumab, vincristine sulfate, vinorelbineditartrate, vorinostat, WT1 126-134 peptide vaccine, WT-1 analog peptidevaccine, yttrium-90 ibritumomab tiuxetan, yttrium-90 humanizedepratuzumab, and any combinations thereof.

Other examples of therapeutic procedures used to treat WM includeperipheral blood stem cell transplantation, autologous hematopoieticstem cell transplantation, autologous bone marrow transplantation,antibody therapy, biological therapy, enzyme inhibitor therapy, totalbody irradiation, infusion of stem cells, bone marrow ablation with stemcell support, in vitro-treated peripheral blood stem celltransplantation, umbilical cord blood transplantation, immunoenzymetechniques, low-LET cobalt-60 gamma ray therapy, bleomycin, conventionalsurgery, radiation therapy, and nonmyeloablative allogeneichematopoietic stem cell transplantation.

Diffuse Large B-cell Lymphoma Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating diffuse large B-cell lymphoma (DLBCL), which includecyclophosphamide, doxorubicin, vincristine, prednisone, anti-CD20monoclonal antibodies, etoposide, bleomycin, many of the agents listedfor WM, and any combination thereof, such as ICE and R-ICE.

Chronic Lymphocytic Leukemia Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating chronic lymphocytic leukemia (CLL), which include chlorambucil,cyclophosphamide, fludarabine, pentostatin, cladribine, doxorubicin,vincristine, prednisone, prednisolone, alemtuzumab, many of the agentslisted for WM, and combination chemotherapy and chemoimmunotherapy,including the following common combination regimens: CVP, R-CVP, ICE,R-ICE, FCR, and FR.

Myelofibrosis Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating myelofibrosis, which include hedgehog inhibitors, histonedeacetylase (HDAC) inhibitors, and tyrosine kinase inhibitors.Non-limiting examples of hedgehog inhibitors are saridegib andvismodegib.

Examples of HDAC inhibitors include, but are not limited to, pracinostatand panobinostat.

Non-limiting examples of tyrosine kinase inhibitors includelestaurtinib, bosutinib, imatinib, gilteritinib, radotinib, andcabozantinib.

Hyperproliferative Disease Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating a hyper-proliferative disease, which include gemcitabine,nab-paclitaxel, and gemcitabine/nab-paclitaxel with a JAK inhibitorand/or PI3K6 inhibitor.

Bladder Cancer Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating bladder cancer, which include atezolizumab, carboplatin,cisplatin, docetaxel, doxorubicin, fluorouracil (5-FU), gemcitabine,idosfamide, Interferon alfa-2b, methotrexate, mitomycin, nab-paclitaxel,paclitaxel, pemetrexed, thiotepa, vinblastine, and any combinationsthereof.

Breast Cancer Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating breast cancer, which include albumin-bound paclitaxel,anastrozole, capecitabine, carboplatin, cisplatin, cyclophosphamide,docetaxel, doxorubicin, epirubicin, everolimus, exemestane,fluorouracil, fulvestrant, gemcitabine, Ixabepilone, lapatinib,Letrozole, methotrexate, mitoxantrone, paclitaxel, pegylated liposomaldoxorubicin, pertuzumab, tamoxifen, toremifene, trastuzumab,vinorelbine, and any combinations thereof.

Triple Negative Breast Cancer Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating triple negative breast cancer, which include cyclophosphamide,docetaxel, doxorubicin, epirubicin, fluorouracil, paclitaxel, andcombinations thereof.

Colorectal Cancer Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating colorectal cancer, which include bevacizumab, capecitabine,cetuximab, fluorouracil, irinotecan, leucovorin, oxaliplatin,panitumumab, ziv-aflibercept, and any combinations thereof.

Castration-Resistant Prostate Cancer Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating castration-resistant prostate cancer, which includeabiraterone, cabazitaxel, docetaxel, enzalutamide, prednisone,sipuleucel-T, and any combinations thereof.

Esophageal and Esophagogastric Junction Cancer Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating esophageal and esophagogastric junction cancer, which includecapecitabine, carboplatin, cisplatin, docetaxel, epirubicin,fluoropyrimidine, fluorouracil, irinotecan, leucovorin, oxaliplatin,paclitaxel, ramucirumab, trastuzumab, and any combinations thereof.

Gastric Cancer Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating gastric cancer, which include capecitabine, carboplatin,cisplatin, docetaxel, epirubicin, fluoropyrimidine, fluorouracil,Irinotecan, leucovorin, mitomycin, oxaliplatin, paclitaxel, ramucirumab,trastuzumab, and any combinations thereof.

Head & Neck Cancer Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating head & neck cancer, which include afatinib, bleomycin,capecitabine, carboplatin, cetuximab, cisplatin, docetaxel,fluorouracil, gemcitabine, hydroxyurea, methotrexate, nivolumab,paclitaxel, pembrolizumab, vinorelbine, and any combinations thereof.

Hepatobiliary Cancer Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating hepatobiliary cancer, which include capecitabine, cisplatin,fluoropyrimidine, 5-fluorourcil, gemecitabine, oxaliplatin, sorafenib,and any combinations thereof.

Hepatocellular Carcinoma Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating hepatocellular carcinoma, which include capecitabine,doxorubicin, gemcitabine, sorafenib, and any combinations thereof.

Non-Small Cell Lung Cancer Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating non-small cell lung cancer (NSCLC), which include afatinib,albumin-bound paclitaxel, alectinib, bevacizumab, bevacizumab,cabozantinib, carboplatin, cisplatin, crizotinib, dabrafenib, docetaxel,erlotinib, etoposide, gemcitabine, nivolumab, paclitaxel, pembrolizumab,pemetrexed, ramucirumab, trametinib, trastuzumab, vandetanib,vemurafenib, vinblastine, vinorelbine, and any combinations thereof.

Small Cell Lung Cancer Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating small cell lung cancer (SCLC), which include bendamustime,carboplatin, cisplatin, cyclophosphamide, docetaxel, doxorubicin,etoposide, gemcitabine, ipillimumab, irinotecan, nivolumab, paclitaxel,temozolomide, topotecan, vincristine, vinorelbine, and any combinationsthereof.

Melanoma Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating melanoma, which include albumin bound paclitaxel, carboplatin,cisplatin, cobiemtinib, dabrafenib, dacrabazine, IL-2, imatinib,interferon alfa-2b, ipilimumab, nitrosourea, nivolumab, paclitaxel,pembrolizumab, pilimumab, temozolomide, trametinib, vemurafenib,vinblastine, and any combinations thereof.

Ovarian Cancer Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating ovarian cancer, which include 5-flourouracil, albumin boundpaclitaxel, altretamine, anastrozole, bevacizumab, capecitabine,carboplatin, cisplatin, cyclophosphamide, docetaxel, doxorubicin,etoposide, exemestane, gemcibabine, ifosfamide, irinotecan, letrozole,leuprolide acetate, liposomal doxorubicin, megestrol acetate, melphalan,olaparib, oxaliplatin, paclitaxel, Pazopanib, pemetrexed, tamoxifen,topotecan, vinorelbine, and any combinations thereof.

Pancreatic Cancer Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating pancreatic cancer, which include 5-fluorourcil, albumin-boundpaclitaxel, capecitabine, cisplatin, docetaxel, erlotinib,fluoropyrimidine, gemcitabine, irinotecan, leucovorin, oxaliplatin,paclitaxel, and any combinations thereof.

Renal Cell Carcinoma Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating renal cell carcinoma, which include axitinib, bevacizumab,cabozantinib, erlotinib, everolimus, levantinib, nivolumab, pazopanib,sorafenib, sunitinib, temsirolimus, and any combinations thereof.

VII. Compound Preparation

Some embodiments of the present disclosure are directed to processes andintermediates useful for preparing the compounds provided herein orpharmaceutically acceptable salts thereof.

Compounds described herein can be purified by any of the means known inthe art, including chromatographic means, such as high performanceliquid chromatography (HPLC), preparative thin layer chromatography,flash column chromatography and ion exchange chromatography. Anysuitable stationary phase can be used, including normal and reversedphases as well as ionic resins. Most typically the disclosed compoundsare purified via silica gel and/or alumina chromatography.

During any of the processes for preparation of the compounds providedherein, it may be necessary and/or desirable to protect sensitive orreactive groups on any of the molecules concerned. This may be achievedby means of conventional protecting groups as described in standardworks, such as T. W. Greene and P. G. M. Wuts, “Protective Groups inOrganic Synthesis,” 4^(th) ed., Wiley, New York 2006. The protectinggroups may be removed at a convenient subsequent stage.

Exemplary chemical entities useful in methods of the embodiments willnow be described by reference to illustrative synthetic schemes fortheir general preparation herein and the specific examples that follow.Artisans will recognize that, to obtain the various compounds herein,starting materials may be suitably selected so that the ultimatelydesired substituents will be carried through the reaction scheme with orwithout protection as appropriate to yield the desired product.Alternatively, it may be necessary or desirable to employ, in the placeof the ultimately desired substituent, a suitable group that may becarried through the reaction scheme and replaced as appropriate with thedesired substituent. Furthermore, one of skill in the art will recognizethat the transformations shown in the schemes below may be performed inany order that is compatible with the functionality of the particularpendant groups. Each of the reactions depicted in the general schemes ispreferably run at a temperature from about 0° C. to the refluxtemperature of the organic solvent used.

The methods of the present disclosure generally provide a specificenantiomer or diastereomer as the desired product, although thestereochemistry of the enantiomer or diastereomer was not determined inall cases. When the stereochemistry of the specific stereocenter in theenantiomer or diastereomer is not determined, the compound is drawnwithout showing any stereochemistry at that specific stereocenter eventhough the compound can be substantially enantiomerically ordisatereomerically pure.

Representative syntheses of compounds of the present disclosure aredescribed in the schemes below, and the particular examples that follow.

LIST OF ABBREVIATIONS AND ACRONYMS

Abbreviation Meaning ° C. Degree Celsius Ac Acetyl MeCN AcetonitrileAcOH Acetic acid ATP Adenosine triphosphate Boc tert-butyloxycarbonyl brBroad ca circa Cy cyclohexyl d Doublet or deuterated DCM or CH₂Cl₂Dichloromethane dd Doublet of doublets DMF Dimethylformamide DMSODimethylsulfoxide dppf 1,1’-Bis(diphenylphosphino)ferrocene dtDoublet-triplet equiv Equivalents Et Ethyl EA or EtOAc Ethyl acetate gGrams Hal Halogen HPLC High pressure liquid chromatography hr or h orhrs Hours Hz Hertz J Coupling constant (MHz) K₂CO₃ Potassium carbonateKg or kg Kilogram L Liter LCMS or LC-MS Liquid chromatography-massspectrometry M Molar m multiplet M+ Mass peak M + H Mass peak plushydrogen Me Methyl MeOH Methanol mg Milligram MHz Megahertz ml or mLMilliliter mM Millimolar mmol Millimole mol Mole MS Mass spectroscopy Msmethanesulfonyl N Normal NaH Sodium hydride NBS N-Bromosuccinimide n-Buor Bu Butyl NH₄C1 Ammonium Chloride NMR Nuclear magnetic resonance NMPN-methylpyrrolidinone Pd-C/ Pd/C Palladium on Carbon PE Petroleum etherPh Phenyl q Quartet RT or rt Room temperature s Singlet sat. Saturatedsec second(s) t Triplet t-Bu or tert-Bu or t-butyl tert-Butyl TFATrifluoroacetic acid THF Tetrahydrofuran δ Chemical shift (ppm) μL or μlMicroliter μM MicromolarSynthesis of the Compounds

The compounds of the present application may be prepared using themethods disclosed herein and modifications thereof, which will beapparent given the disclosure herein. Known synthetic methods may beused in addition to the procedures described herein. The synthesis oftypical compounds described herein may be accomplished as described inthe following examples. If available, reagents may be purchasedcommercially, e.g., from Sigma Aldrich or other chemical suppliers. Ingeneral, compounds described herein are typically stable and isolatableat room temperature and pressure.

Compounds were named using ChemBioDraw Ultra Version 14.0.

When production of starting materials is not particularly described, thecompounds are either known or may be prepared analogously to methodsknown in the art or as disclosed in the Examples. One of skill in theart will appreciate that synthetic methodologies described herein areonly representative of methods for preparation of the compoundsdescribed herein, and that other known methods and variants of methodsdescribed herein may be used. The methods or features described invarious Examples may be combined or adapted in various ways to provideadditional ways of making the compounds described herein.

General Synthesis

Typical embodiments of compounds described herein may be synthesizedusing the general reaction schemes described below. It will be apparentgiven the description herein that the general schemes may be altered bysubstitution of the starting materials with other materials havingsimilar structures to result in products that are correspondinglydifferent. Descriptions of syntheses follow to provide numerous examplesof how the starting materials may vary to provide correspondingproducts. Given a desired product for which the substituent groups aredefined, the necessary starting materials generally may be determined byinspection. Starting materials are typically obtained from commercialsources or synthesized using published methods. For synthesizingcompounds which are embodiments described in the present disclosure,inspection of the structure of the compound to be synthesized willprovide the identity of each substituent group. The identity of thefinal product will generally render apparent the identity of thenecessary starting materials by a simple process of inspection, giventhe examples herein. Group labels (e.g. R¹, R^(a), R^(b)) used in thereaction schemes herein are for illustrative purposes only and unlessotherwise specified do not necessarily match by name or function thelabels used elsewhere to describe compounds of Formula I, I-Z, I-E,II-Z, IIa-Z, IIb-Z, III-Z, or IIIa-Z or aspects or fragments thereof.

Synthetic Reaction Parameters

The compounds of this disclosure can be prepared from readily availablestarting materials using, for example, the following general methods andprocedures. It will be appreciated that where typical or preferredprocess conditions (i.e., reaction temperatures, times, mole ratios ofreactants, solvents, pressures, etc.) are given, other processconditions can also be used unless otherwise stated. Optimum reactionconditions may vary with the particular reactants or solvent used, butsuch conditions can be determined by one skilled in the art byoptimization procedures.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary to prevent certainfunctional groups from undergoing undesired reactions. Suitableprotecting groups for various functional groups as well as suitableconditions for protecting and deprotecting particular functional groupsare known in the art. For example, numerous protecting groups aredescribed in T. W. Greene and G. M. Wuts (1999) Protecting Groups inOrganic Synthesis, 3^(rd) Edition, Wiley, New York, and references citedtherein.

The terms “solvent”, “inert organic solvent”, or “inert solvent” referto a solvent inert under the conditions of the reaction being describedin conjunction therewith (including, for example, benzene, toluene,acetonitrile, tetrahydrofuran (“THF”), dimethylformamide (“DMF”),chloroform, methylene chloride (or dichloromethane), diethyl ether,methanol, and the like). Unless specified to the contrary, the solventsused in the reactions of the present invention are inert organicsolvents, and the reactions are carried out under an inert gas,preferably nitrogen or argon.

Reaction Scheme I

The compounds of Formula I or I-Z may be prepared using methods similarto those shown in Reaction Scheme I.

Step 1—Preparation of a Compound of Formula 2

The compounds of formula 2 are commercially available or can be made byhalogenating compounds 1 by methods known in the art. Compounds 1 arecommercially available or can be made by methods known in the art.Compounds 1 may be mixed in a suitable solvent, such as TFA, in thepresence of NBS. After stirring at temperatures between 0° C. and 100°C. for between 10 min and 24 h or until reaction is complete, thereaction is allowed to equilibrate to room temperature. The compound offormula 2 can be obtained by filtration, precipitation, or extraction.To extract the compounds of formula 2, an organic solvent such as ethylacetate may be added, followed by washing with water and brine. Theorganic phase can be concentrated to obtain the compounds of formula 2.The compounds of formula 2 may be purified by any suitable methods, suchas chromatography on silica gel, trituration, precipitation, orcrystallization.

Step 2—Preparation of a Compound of Formula 4

The compounds of formula 4 may be prepared by combining compounds offormula 2 and formula 3. The compounds of formula 3 are commerciallyavailable or may be prepared by borylating the corresponding iodide,bromide, or chloride by methods known in the art. A compound of formula2 and formula 3 may be mixed in a suitable solvent, such as DMF, in thepresence of an appropriate base, such as potassium carbonate, palladiumcatalyst, such as PdCl₂(dppf), and co-solvent, such as water. Afterstirring at a temperature between 23° C. and 110° C. for between 10 minand 24 h or until the reaction is complete, the reaction is allowed tocool to room temperature. To extract the compounds of formula 4, anorganic solvent, such as ethyl acetate may be added, followed by washingwith water and brine. The organic phase can be concentrated to obtainthe compounds of formula 4. The compounds of formula 4 may be purifiedby a suitable method, such as chromatography on silica gel, trituration,precipitation, or crystallization.

Step 3—Preparation of a Compound of Formula I

The compounds of Formula I or I-Z can be made by combining the compoundsof formula 4 and compounds of formula 5. Compound of formula 5 arecommercially available or can be prepared by methods known in the art.Compounds of formula 4 and 5 may be combined in a suitable solvent, suchas ethanol, in the presence of a suitable amine, such as piperidine orpyrrolidine. After stirring at a temperature between 60° C. and 155° C.,with or without the use of a microwave reactor, for between 15 min and24 hours, the reaction is allowed to cool to room temperature. The cruderesidue is dissolved in a suitable solvent mixture, such as 1:1dichloromethane:TFA and stirred at temperatures between 23° C. and 100°C. for 15 minutes to 24 hours. The mixtures are then cooled to roomtemperature. Compounds of Formula I may be isolated by concentrationunder reduced pressure, and may be purified by a suitable method, suchas chromatography on silica gel, reverse phase chromatography,trituration, precipitation, or crystallization.

Reaction Scheme II

The compounds of Formula IIb-Z may be prepared using methods similar tothose shown in Reaction Scheme II.

Step 1—Preparation of a Compound of Formula 2

The compounds of formula 2 are commercially available or can be made asdescribed above for Reaction Scheme I.

Step 2—Preparation of a Compound of Formula 4

The compounds of formula 4 may be prepared by combining compounds offormula 2 and formula 3 as described above for Reaction Scheme I. Thecompounds of formula 3 are commercially available or may be prepared asdescribed above for Reaction Scheme I.

Step 3—Preparation of a Compound of Formula IIb-Z

The compounds of Formula IIb-Z can be made by combining the compounds offormula 4 and compounds of formula 6. Compound of formula 6 arecommercially available or can be prepared by methods known in the art.Compounds of formula 4 and 6 may be combined in a suitable solvent, suchas ethanol, in the presence of a suitable amine, such as piperidine orpyrrolidine. After stirring at a temperature between 60° C. and 155° C.,with or without the use of a microwave reactor, for between 15 min and24 hours, the reaction is allowed to cool to room temperature. The cruderesidue is dissolved in a suitable solvent mixture, such as 1:1dichloromethane:TFA and stirred at temperatures between 23° C. and 100°C. for 15 minutes to 24 hours. The mixtures are then cooled to roomtemperature. Compounds of Formula IIb-Z may be isolated by concentrationunder reduced pressure. The compound of Formula IIb-Z may be purified byany suitable methods, such as chromatography on silica gel, reversephase chromatography, trituration, precipitation, or crystallization.

Reaction Scheme III

The compounds of Formula IIIa may be prepared using methods similar tothose shown in Reaction Scheme III.

Step 1—Preparation of a Compound of Formula 2

The compounds of formula 2 are commercially available or can be made asdescribed above for Reaction Scheme I.

Step 2—Preparation of a Compound of Formula 4

The compounds of formula 4 may be prepared by combining compounds offormula 2 and formula 3 as described above for Reaction Scheme I. Thecompounds of formula 3 are commercially available or may be prepared asdescribed above for Reaction Scheme I.

Step 3—Preparation of a Compound of Formula IIIa-Z

The compounds of Formula IIIa-Z can be made by combining the compoundsof formula 4 and compounds of formula 7. Compound of formula 7 arecommercially available or can be prepared by methods known in the art.Compounds of formula 4 and 7 may be combined in a suitable solvent, suchas ethanol, in the presence of a suitable amine, such as piperidine orpyrrolidine. After stirring at a temperature between 60° C. and 155° C.,with or without the use of a microwave reactor, for between 15 min and24 hours, the reaction is allowed to cool to room temperature. The cruderesidue is dissolved in a suitable solvent mixture, such as 1:1dichloromethane:TFA and stirred at temperatures between 23° C. and 100°C. for 15 minutes to 24 hours. The mixtures are then cooled to roomtemperature. Compounds of Formula IIIa-Z may be isolated byconcentration under reduced pressure. The compounds of Formula IIIa-Zmay be purified by any suitable methods known in the art, such aschromatography on silica gel, reverse phase chromatography, trituration,precipitation, or crystallization.

General Procedures

Procedure 1: General Preparation of Intermediate 13 and RelatedCompounds.

A. Preparation of ethyl2-((5-bromo-4-methyl-3-nitropyridin-2-yl)oxy)acetate (9)

Ethyl glycolate (13.17 mL, 139.2 mmol, 7.0 equiv.) was dissolved in THF(5 mL) and cooled to 0° C. Potassium tert-butoxide (13.39 g, 119.3 mmol,6.0 equiv.) was added to the solution in 3 portions. After an additional5 minutes at 0° C., 8 (5.0 g, 19.88 mmol, 1.0 equiv.) was added. After 2minutes of stirring at 0° C. the reaction was quenched by the additionof 15 mL of saturated ammonium chloride. The aqueous layer was thenextracted with EtOAc (4×30 mL). The combined organic layers were driedover sodium sulfate and concentrated in vacuo. The crude product waspurified by column chromatography (EtOAc/Hexanes 0-50%) to afford 9.LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₁₀H₁₂BrN₂O₅: 319.0; found: 319.1.

B. Preparation of 7-bromo-8-methyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one(10)

9 (1.3 g, 4.07 mmol, 1.0 equiv.) and iron metal (1.14 g, 20.4 mmol, 5.0equiv.) were dissolved in EtOAc (10 mL) and AcOH (5 mL). A refluxcondenser was fitted and the reaction vessel was heated to 85° C. After16 hours, the reaction mixture was cooled to room temperature andbasified with saturated sodium carbonate solution. The aqueous layer wasextracted with EtOAc (4×20 mL). The combined organic layers were driedover sodium sulfate and concentrated in vacuo to afford 10 which wasused without further purification. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₈H₈BrN₂O₂: 243.0; found: 243.1.

C. Preparation of7-bromo-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (11)

A vial with a stir bar was charged with 10 (331 mg, 1.36 mmol, 1.0equiv.) then sealed. The vessel was cooled to 0° C. and a THF solutionof borane (4.54 mL, 0.9 M, 3 equiv.) was added slowly through theseptum. The sealed vessel was then heated to 50° C. After 30 minutes,the vessel was cooled to room temperature then saturated NaHCO₃ wasadded dropwise until gas evolution ceased. The aqueous layer was thenextracted with EtOAc (4×5 mL). The combined organic layers were driedover sodium sulfate and concentrated in vacuo to afford 11 which wasused without further purification. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₈H₁₀BrN₂O: 229.0; found: 229.1.

D. Preparation of tert-butyl7-bromo-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate(12)

11 (630 mg, 2.75 mmol, 1.0 equiv.) was dissolved in THF (10 mL) andcooled to 0° C. To this solution was added a 1.5 M solution of LiHMDS inTHF (5.5 mL, 8.25 mmol, 3 equiv.) dropwise over 5 minutes. After 10minutes at 0° C., Boc₂O (1.8 g, 8.25 mmol, 3.0 equiv.) was added in asingle portion. The reaction mixture was allowed to warm to roomtemperature. After 15 minutes, the reaction was quenched by the additionof saturated ammonium chloride (10 mL). The aqueous layer was extractedwith EtOAc (4×15 mL). The combined organic layers were dried over sodiumsulfate and concentrated in vacuo. The crude oil was purified by columnchromatography (EtOAc/Hexanes 0-50%) to afford 12. LCMS-ESI⁺ (m/z):[M+H]⁺ calcd for C₁₃H₁₈BrN₂O₃: 329.0; found: 329.2.

E. Preparation of tert-butyl8-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate(13)

A screw cap vial with a stir bar was charged with 12 (227 mg, 0.84 mmol,1.0 equiv.), dipinacoldiboron (427 mg, 1.68 mmol, 2.0 equiv.),Pd(dppf)Cl₂.CH₂Cl₂ (137.4 mg, 0.17 mmol, 20 mol %) and KOAc (289 mg,2.94 mmol, 3.5 equiv.). The vial was sealed and dioxane (4 mL) was addedvia syringe. The reaction vessel was then placed under vacuum until gasevolution was observed and then refilled with argon. The vessel wasevacuated and refilled four times in total. The reaction vessel was thenheated to 100° C. for 2 hours. The reaction mixture was then filteredthrough celites and concentrated in vacuo. The crude material waspurified by column chromatography (EtOAc/Hexanes 0-20%) to afford 13.LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₁₉H₃₀BN₂O₅: 377.2; found: 377.3.

Procedure 2: General Preparation of Intermediate 14 and RelatedCompounds.

A. Preparation of tert-butyl8-methyl-7-(2-oxoindolin-5-yl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate(14)

A mixture of 13 (400 mg, 1.2 mmol, 1.35 equiv.) and 5-bromoindolin-2-one(166 mg, 0.79 mmol) was dissolved with dioxane (6 mL) and water (0.6 mL)in a 40 mL vial. To the vessel were added potassium carbonate (218 mg,1.58 mmol, 2.0 equiv.) and Pd(dppf)Cl₂ (65.6 mg, 0.08 mmol, 10 mol %),and nitrogen was bubbled through the mixture for 2 minutes. Afterstirring for 2 hours at 100° C., or until complete by LCMS analysis, thereaction mixture was cooled to room temperature, diluted with ethylacetate, and filtered through celite. The filtrate was washed once withwater and once with brine. The organic layer was dried over magnesiumsulfate, filtered, and concentrated under vacuum. The crude residue waspurified by silica gel chromatography using a 0-10% MeOH in DCM eluentto afford 14. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₁H₂₄N₃O₄: 382.2;found: 382.3.

Procedure 3: General Preparation of Intermediate 15 and RelatedCompounds.

A. Preparation of tert-butyl(Z)-7-(3-((1H-pyrrol-2-yl)methylene)-2-oxoindolin-5-yl)-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate(15)

In an oven-dried 2-dram vial were added 14 (35 mg, 0.09 mmol),1H-pyrrole-2-carbaldehyde, ethanol (1 mL), and piperidine (1 drop). Thevessel was heat to 90° C. for 30 minutes. Upon cooling to roomtemperature, the contents were concentrated under vacuum and usingwithout further purification.

Procedure 4: General Preparation of Intermediate 17 and RelatedCompounds.

A. Preparation of(Z)-3-(1-(1H-pyrrol-2-yl)ethylidene)-5-bromoindolin-2-one (16)

To a microwave vial were added 5-bromoindolin-2-one (0.24 mmol, 50 mg)and 1-(1H-pyrrol-2-yl)ethan-1-one (0.31 mmol, 34 mg) with pyrrolidine (1mL) and heated in a microwave reactor for 1 hour at 150° C. The reactionmixture was concentrated under reduced pressure and purified by reversedphase HPLC to give(Z)-3-(1-(1H-pyrrol-2-yl)ethylidene)-5-bromoindolin-2-one (16).LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₁₄H₁₁BrN₂O: 302.0; found: 302.2.

B. Preparation of tert-butyl(Z)-7-(3-(1-(1H-pyrrol-2-yl)ethylidene)-2-oxoindolin-5-yl)-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate(17)

(Z)-3-(1-(1H-pyrrol-2-yl)ethylidene)-5-bromoindolin-2-one (16) (18 mg,0.06 mmol), tert-butyl8-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate(13) (28 mg, 0.08 mmol), potassium carbonate (41 mg, 0.17 mmol), andPd(dppf)Cl₂ (4.8 mg, 0.006 mmol) were combined with dioxane (3 mL) andH₂O (0.3 mL). The mixture was purged with nitrogen gas and heated at100° C. on heating block for 30 min. The reaction mixture was dilutedwith ethyl acetate, filtered through a pad of celite, concentrated, andpurified by reversed phase HPLC to give(Z)-3-(1-(1H-pyrrol-2-yl)ethylidene)-5-bromoindolin-2-one (17).LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₇H₂₈N₄O₄: 472.2; found: 472.2.

Procedure 5: General Procedure for Boc Deprotection((Z)-3-((1H-pyrrol-2-yl)methylene)-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)indolin-2-one)(Example 29)

To a 2-dram vial was added unpurified 15 (20 mg), TFA (1 mL) and DCM (1mL). The mixture was stirred at room temperature for 30 minutes. Thesolution was concentrated under vacuum and purified by reverse phaseHPLC. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₁H₁₉N₄O₂: 359.1; found: 359.2.

EXAMPLES Example 1:(Z)—N-(2-(diethylamino)ethyl)-5-((6-fluoro-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide(C1)

This compound was prepared as outlined above in procedures 1, 2, 3, and5 using commercially available intermediates5-bromo-6-fluoroindolin-2-one andN-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide.

¹H NMR (400 MHz, Methanol-d4) δ 7.60 (s, 1H), 7.57 (d, J=7.0 Hz, 1H),7.43 (s, 1H), 6.81 (d, J=9.8 Hz, 1H), 4.51 (t, J=4.4 Hz, 2H), 3.72 (t,J=6.1 Hz, 2H), 3.56 (s, 2H), 3.35 (dd, J=15.3, 7.0 Hz, 8H), 2.52 (s,3H), 2.44 (s, 3H), 2.08 (d, J=1.6 Hz, 3H), 1.37 (t, J=7.3 Hz, 6H).LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₃₀H₃₅FN₆O₃: 547.3; found: 547.6.

Example 2:(Z)-3-((2-methyl-1H-imidazol-5-yl)methylene)-5-(5-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)indolin-2-one(C2)

This compound was prepared as outlined above in procedures 2, 3, and 5using commercially available intermediate2-methyl-H-imidazole-5-carbaldehyde and(5-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)boronic acid.

¹H NMR (400 MHz, Methanol-d4) δ 7.93 (s, 1H), 7.69 (s, 1H), 7.54 (s,1H), 7.18 (d, J=7.8 Hz, 1H), 6.97 (d, J=8.0 Hz, 1H), 6.63 (d, J=8.2 Hz,1H), 6.52 (d, J=8.3 Hz, 1H), 4.22-4.15 (m, 2H), 3.49-3.42 (m, 3H), 2.76(s, 3H), 2.02 (s, 3H). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₂H₂₀N₄O₂:373.2; found: 373.4.

Example 3:(Z)-6-methyl-3-((2-methyl-1H-imidazol-5-yl)methylene)-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)indolin-2-one(C3)

This compound was prepared as outlined above in procedures 1, 2, 3, and5 using commercially available intermediates5-bromo-6-methylindolin-2-one and 2-methyl-1H-imidazole-5-carbaldehyde.

¹H NMR (400 MHz, Methanol-d4) δ 7.94 (s, 1H), 7.63 (s, 1H), 7.45 (s,1H), 7.37 (s, 1H), 6.96 (s, 1H), 4.60 (t, J=4.5 Hz, 2H), 3.61 (td,J=4.3, 2.4 Hz, 2H), 2.76 (s, 3H), 2.12 (s, 3H), 2.01 (s, 3H). LCMS-ESI⁺(m/z): [M+H]⁺ calcd for C₂₂H₂₂N₅O₂: 388.2; found: 388.2.

Example 4:(Z)-7-fluoro-4-methyl-3-((2-methyl-1H-imidazol-5-yl)methylene)-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)indolin-2-one(C4)

A. Preparation of 7-fluoro-4-methylindolin-2-one (18)

To a 40 mL vial was added commercially available4-bromo-7-fluoroindolin-2-one (400.0 mg, 1.74 mmol, 1.0 equiv.),2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (327 mg, 0.37 mL, 2.6mmol, 1.5 equiv.), Pd G3 SPhos (27.1 mg, 0.03 mmol, 0.02 equiv.), andpotassium phosphate tribasic (737.3 mg, 3.48 mmol, 2.0 equiv.). The vialwas then charged with a stir bar, toluene (3.6 mL), and water (0.4 mL)sequentially. The vial was then sealed with a teflon cap. The sealedvessel was then subjected to four cycles of evacuation until gasevolution from solution was observed and refilling with argon. Thevessel was then heated to 100° C. for 1 hour. After cooling to roomtemperature, the reaction mixture was diluted with ethyl acetate (2 mL)and water (1 mL). The organic layer was separated, and the aqueous layerwas extracted twice more with ethyl acetate. The combined organic layerswere dried over sodium sulfate and concentrated in vacuo. Purificationby silica gel chromatography (EtOAc/Hexanes) afforded7-fluoro-4-methylindolin-2-one (18). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₉H8FNO: 166.1; found: 166.1.

B. Preparation of 5-bromo-7-fluoro-4-methylindolin-2-one

To 40 mL vial was added 7-fluoro-4-methylindolin-2-one (18) (100 mg,0.61 mmol, 1 equiv.), a stir bar, and MeCN (3 mL) sequentially. The vialwas cooled to 0° C. NBS (129.3 mg, 0.73 mmol, 1.2 equiv.) was then addedin a single portion and the reaction was allowed to warm to roomtemperature overnight. Water was then added to the reaction and a beigeprecipitate formed. The precipitate was isolated by vacuum filtrationthen washed sequentially with water, hexanes, and ether. The solids werefurther dried under vacuum to afford5-bromo-7-fluoro-4-methylindolin-2-one (19). LCMS-ESI⁺ (m/z): [M+H]⁺calcd for C₉H₇BrFNO: 244.0; found: 244.2.

C. Preparation of(Z)-7-fluoro-4-methyl-3-((2-methyl-1H-imidazol-5-yl)methylene)-5-(8-methyl-2,3-dihydro-TH-pyrido[2,3-b][1,4]oxazin-7-yl)indolin-2-one(C4)

This compound was prepared as outlined above in procedures 1, 2, 3, and5 using 7-fluoro-4-methylindolin-2-one (19) and commercially availableintermediate 2-methyl-H-imidazole-5-carbaldehyde.

¹H NMR (400 MHz, Methanol-d4) δ 8.16 (s, 1H), 7.85 (s, 1H), 7.39 (s,1H), 7.03 (d, J=9.9 Hz, 1H), 4.61 (t, J=4.5 Hz, 2H), 3.62 (td, J=4.3,2.0 Hz, 2H), 2.78 (s, 3H), 2.34 (s, 3H), 2.02 (s, 3H). LCMS-ESI⁺ (m/z):[M+H]⁺ calcd for C₂₂H₂₁FN₅O₂: 406.2; found: 406.1.

Example 5:(Z)-5-(2,3-dihydro-H-pyrido[2,3-b][1,4]oxazin-7-yl)-7-fluoro-4-methyl-3-((2-methyl-TH-imidazol-5-yl)methylene)indolin-2-one(C5)

This compound was prepared as outlined above for(Z)-7-fluoro-4-methyl-3-((2-methyl-1H-imidazol-5-yl)methylene)-5-(8-methyl-2,3-dihydro-H-pyrido[2,3-b][1,4]oxazin-7-yl)indolin-2-oneusing commercially available intermediate(2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)boronic acid.

¹H NMR (400 MHz, Methanol-d4) δ 8.16 (s, 1H), 7.85 (s, 1H), 7.38 (d,J=2.0 Hz, 1H), 7.12 (d, J=2.0 Hz, 1H), 7.08 (d, J=10.2 Hz, 1H),4.59-4.49 (m, 2H), 3.53-3.48 (m, 2H), 2.77 (s, 3H), 2.49 (s, 3H).LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₁H₁₉FN₅O₂: 392.1; found: 392.1.

Example 6:(Z)-3-((2-ethyl-4-methyl-1H-imidazol-5-yl)methylene)-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)indolin-2-one(C6)

This compound was prepared as outlined above in procedures 1, 2, 3, and5 using commercially available intermediate2-ethyl-4-methyl-1H-imidazole-5-carbaldehyde.

¹H NMR (400 MHz, Methanol-d4) δ 7.78 (d, J=5.6 Hz, 2H), 7.40 (s, 1H),7.27-7.22 (m, 1H), 7.06 (d, J=8.0 Hz, 1H), 4.50 (t, J=4.4 Hz, 2H),3.59-3.52 (m, 2H), 3.08 (q, J=7.6 Hz, 2H), 2.59 (s, 3H), 2.15 (s, 3H),1.48 (t, J=7.6 Hz, 3H). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₃H₂₄N₅O₂:402.2; found: 402.5.

Example 7:(Z)-6-chloro-3-((2-methyl-1H-imidazol-5-yl)methylene)-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)indolin-2-one(C7)

This compound was prepared as outlined above in procedures 1, 2, 3, and5 using commercially available intermediates5-bromo-6-chloroindolin-2-one and 2-methyl-1H-imidazole-5-carbaldehyde.

¹H NMR (400 MHz, Methanol-d4) δ 7.99 (s, 1H), 7.72 (s, 1H), 7.62 (s,1H), 7.36 (s, 1H), 7.15 (s, 1H), 4.52 (t, J=4.5 Hz, 2H), 3.56 (q, J=4.6Hz, 2H), 2.76 (s, 3H), 2.01 (s, 3H). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₂₁H₁₉ClN₅O₂: 408.1; found: 408.9.

Example 8:(Z)-6-fluoro-3-((2-methyl-H-imidazol-5-yl)methylene)-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)indolin-2-one(C8)

This compound was prepared as outlined above in procedures 1, 2, 3, and5 using commercially available intermediates5-bromo-6-fluoroindolin-2-one and 2-methyl-1H-imidazole-5-carbaldehyde.

¹H NMR (400 MHz, Methanol-d4) δ 7.96 (s, 1H), 7.69 (s, 1H), 7.61 (d,J=7.0 Hz, 1H), 7.40 (s, 1H), 6.86 (d, J=9.5 Hz, 1H), 4.49 (t, J=4.5 Hz,2H), 3.54 (s, 2H), 2.76 (s, 3H), 2.05 (d, J=1.8 Hz, 3H). LCMS-ESI⁺(m/z): [M+H]⁺ calcd for C₂₁H₁₉FN₅O₂: 392.1; found: 392.4.

Example 9:(Z)—N-(2-(diethylamino)ethyl)-5-((7-fluoro-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide(C9)

This compound was prepared as outlined above in procedures 1, 2, 3, and5 using commercially available intermediates5-bromo-7-fluoroindolin-2-one andN-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide.

¹H NMR (400 MHz, Methanol-d4) δ 7.69 (s, 1H), 7.46-7.41 (m, 2H), 6.93(d, J=10.6 Hz, 1H), 4.52 (t, J=4.4 Hz, 2H), 3.72 (t, J=6.1 Hz, 2H), 3.56(t, J=4.5 Hz, 2H), 3.36 (dd, J=16.0, 7.0 Hz, 6H), 2.53 (s, 3H), 2.46 (s,3H), 2.17 (s, 3H), 1.38 (t, J=7.3 Hz, 6H). LCMS-ESI⁺ (m/z): [M+H]⁺ calcdfor C₃H₃₆FN₆O₃: 547.3; found: 547.6.

Example 10:(Z)-7-fluoro-3-((2-methyl-1H-imidazol-5-yl)methylene)-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)indolin-2-one(C10)

This compound was prepared as outlined above in procedures 1, 2, 3, and5 using commercially available intermediates5-bromo-7-fluoroindolin-2-one and 2-methyl-1H-imidazole-5-carbaldehyde.

¹H NMR (400 MHz, Methanol-d4) δ 8.01 (s, 1H), 7.83 (s, 1H), 7.49 (d,J=1.3 Hz, 1H), 7.43 (s, 1H), 7.14 (dd, J=10.5, 1.4 Hz, 1H), 4.56-4.47(m, 2H), 3.56 (dd, J=5.1, 3.9 Hz, 2H), 2.77 (s, 3H), 2.16 (s, 3H).LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₁H₁₉FN₅O₂: 392.1; found: 392.4.

Example 11:(Z)-3-(1-(1H-imidazol-5-yl)ethylidene)-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)indolin-2-one(C11)

This compound was prepared as outline in procedures 4 and 5 usingcommercially available intermediate 1-(1H-imidazol-5-yl)ethan-1-one.

¹H NMR (400 MHz, Methanol-d4) δ 8.93 (d, J=1.2 Hz, 1H), 8.20 (d, J=1.2Hz, 1H), 7.71 (s, 1H), 7.44 (s, 1H), 7.32-7.27 (m, 1H), 7.10 (d, J=8.0Hz, 1H), 4.51 (d, J=4.5 Hz, 2H), 3.57 (t, J=4.5 Hz, 2H), 2.80 (s, 3H),2.16 (s, 3H). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₁H₂₀N5O₂: 374.2;found: 374.1.

Example 12:(Z)-5-((7-fluoro-4-methyl-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-2-oxoindolin-3-ylidene)methyl)-1H-pyrrole-3-carbonitrile(C12)

This compound was prepared as outlined above for(Z)-7-fluoro-4-methyl-3-((2-methyl-1H-imidazol-5-yl)methylene)-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)indolin-2-oneusing commercially available intermediate5-formyl-1H-pyrrole-3-carbonitrile.

¹H NMR (400 MHz, Methanol-d4) δ 14.12 (s, 1H), 7.85-7.71 (m, 2H), 7.40(s, 1H), 7.19 (t, J=1.8 Hz, 1H), 6.92 (d, J=10.0 Hz, 1H), 4.62 (t, J=4.6Hz, 2H), 3.70-3.55 (m, 2H), 2.32 (s, 3H), 2.03 (s, 3H). LCMS-ESI⁺ (m/z):[M+H]⁺ calcd for C₂₃H₁₉FN₅O₂: 416.1; found: 416.1.

Example 13:(Z)-7-fluoro-4-methyl-3-((4-methyl-H-pyrrol-2-yl)methylene)-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)indolin-2-one(C13)

This compound was prepared as outlined above for(Z)-7-fluoro-4-methyl-3-((2-methyl-1H-imidazol-5-yl)methylene)-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)indolin-2-oneusing commercially available 4-methyl-1H-pyrrole-2-carbaldehyde.

¹H NMR (400 MHz, Methanol-d4) δ 13.34 (s, 1H), 7.78 (s, 1H), 7.38 (s,1H), 7.09 (s, 1H), 6.81 (d, J=10.1 Hz, 1H), 6.69 (s, 1H), 4.62 (t, J=4.5Hz, 2H), 3.63 (td, J=4.3, 2.5 Hz, 2H), 2.31 (s, 3H), 2.15 (s, 3H), 2.03(s, 3H). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₃H₂₂FN₄O₂: 405.2; found:405.1.

Example 14:(Z)-3-((1H-pyrrol-2-yl)methylene)-7-fluoro-4-methyl-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)indolin-2-one(C14)

This compound was prepared as outlined above for(Z)-7-fluoro-4-methyl-3-((2-methyl-1H-imidazol-5-yl)methylene)-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)indolin-2-one.

¹H NMR (400 MHz, Methanol-d4) δ 13.55 (s, 1H), 7.86 (s, 1H), 7.38 (s,1H), 7.28 (td, J=2.7, 1.3 Hz, 1H), 6.88 (dt, J=3.6, 1.5 Hz, 1H), 6.82(d, J=10.1 Hz, 1H), 6.39 (dt, J=3.7, 2.3 Hz, 1H), 4.67-4.52 (m, 2H),3.62 (td, J=4.3, 2.4 Hz, 2H), 2.32 (s, 3H), 2.02 (s, 3H). LCMS-ESI⁺(m/z): [M+H]⁺ calcd for C₂₂H₂₀FN₄O₂: 391.2; found: 391.1.

Example 15:(Z)-3-((2-methyl-H-imidazol-5-yl)methylene)-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)indolin-2-one(C15)

This compound was prepared as outlined above in procedures 1, 2, 3, and5 using commercially available intermediate2-methyl-1H-imidazole-5-carbaldehyde.

¹H NMR (400 MHz, Methanol-d4) δ 7.94 (s, 1H), 7.75 (s, 1H), 7.62 (d,J=1.6 Hz, 1H), 7.38 (s, 1H), 7.25 (dd, J=8.0, 1.6 Hz, 1H), 7.05 (d,J=8.1 Hz, 1H), 4.52-4.42 (m, 2H), 3.57-3.48 (m, 2H), 2.75 (s, 3H), 2.12(s, 3H). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₁H₂₀N₅O₂: 374.2; found:374.4.

Example 16:(Z)—N-(2-(diethylamino)ethyl)-2,4-dimethyl-5-((5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-2-oxoindolin-3-ylidene)methyl)-1H-pyrrole-3-carboxamide(C16)

This compound was prepared as outlined above in procedures 1, 2, 3, and5 using commercially available intermediates andN-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide.

¹H NMR (400 MHz, Methanol-d4) δ 7.64 (s, 1H), 7.59 (d, J=1.6 Hz, 1H),7.42 (s, 1H), 7.11-7.07 (m, 1H), 7.01 (d, J=8.0 Hz, 1H), 4.52 (t, J=4.5Hz, 2H), 3.72 (t, J=6.1 Hz, 2H), 3.57 (t, J=4.4 Hz, 2H), 3.36 (dd,J=15.6, 6.9 Hz, 6H), 2.53 (s, 3H), 2.46 (s, 3H), 2.16 (s, 3H), 1.38 (t,J=7.3 Hz, 6H). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₃₀H₃₆FN₆O₃: 529.3;found: 529.7.

Example 17:(Z)-3-((5-methyl-H-pyrrol-2-yl)methylene)-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)indolin-2-one(C17)

This compound was prepared as outlined above in procedures 1, 2, 3, and5 using commercially available intermediate5-methyl-1H-pyrrole-2-carbaldehyde.

¹H NMR (400 MHz, Methanol-d4) δ 7.55 (s, 1H), 7.47 (s, 1H), 7.41 (s,1H), 7.07-6.99 (m, 2H), 6.76 (s, 1H), 6.13 (d, J=3.3 Hz, 1H), 4.53 (t,J=4.5 Hz, 2H), 3.57 (t, J=4.5 Hz, 2H), 2.40 (s, 3H), 2.17 (s, 3H).LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₂H₂₁N₄O₂: 373.2; found: 373.4.

Example 18:(Z)-3-(isothiazol-5-ylmethylene)-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)indolin-2-one(C18)

This compound was prepared as outlined above in procedures 1, 2, 3, and5 using commercially available intermediate isothiazole-5-carbaldehyde.

¹H NMR (400 MHz, Methanol-d4) δ 8.53 (d, J=1.8 Hz, 1H), 8.15 (s, 1H),7.72 (ddd, J=15.9, 1.8, 0.6 Hz, 2H), 7.44 (s, 1H), 7.26 (dd, J=8.0, 1.7Hz, 1H), 7.04 (dd, J=8.0, 0.6 Hz, 1H), 4.60-4.51 (m, 2H), 3.63-3.54 (m,2H), 2.19 (s, 3H). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₀H₁₆N₄O₂S: 377.1;found: 377.4.

Example 19: (E andZ)-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-3-(thiophen-2-ylmethylene)indolin-2-one(C19)

This compound was prepared as outlined above in procedures 1, 2, 3, and5 using commercially available intermediate thiophene-2-carbaldehyde.

Mixture of 2 isomers; HPLC tR=4.22 min/4.40 min. LCMS-ESI⁺ (m/z): [M+H]⁺calcd for C₂₁H₁₈N₃O₂S: 376.1; found: 376.4.

Example 20:(Z)-3-((4-bromo-1H-pyrrol-2-yl)methylene)-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)indolin-2-one(C20)

This compound was prepared as outlined above in procedures 1, 2, 3, and5 using commercially available intermediate4-bromo-1H-pyrrole-2-carbaldehyde.

¹H NMR (400 MHz, Methanol-d4) δ 7.58 (s, 1H), 7.49 (s, 1H), 7.34 (s,1H), 7.20 (s, 1H), 7.08 (d, J=9.6 Hz, 1H), 6.98 (d, J=8.1 Hz, 1H), 6.79(s, 1H), 4.39 (s, 2H), 3.57 (s, 2H), 2.08 (s, 3H). LCMS-ESI⁺ (m/z):[M+H]⁺ calcd for C₂₁H₁₈BrN₄O₂: 437.1; found: 437.3.

Example 21:(Z)-5-((5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-2-oxoindolin-3-ylidene)methyl)-1H-pyrrole-3-carbonitrile(C21)

This compound was prepared as outlined above in procedures 1, 2, 3, and5 using commercially available intermediate5-formyl-1H-pyrrole-3-carbonitrile.

¹H NMR (400 MHz, Methanol-d4) δ 7.75 (s, 1H), 7.65 (d, J=2.7 Hz, 1H),7.56 (s, 1H), 7.38 (s, 1H), 7.15 (d, J=8.4 Hz, 1H), 7.07 (s, 1H), 7.01(d, J=8.1 Hz, 1H), 4.47 (t, J=4.4 Hz, 2H), 3.54 (t, J=4.4 Hz, 2H), 2.13(s, 3H). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₂H₁₈N₅O₂: 384.1; found:384.4.

Example 22:(Z)-7-chloro-3-((4-methyl-1H-pyrrol-2-yl)methylene)-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)indolin-2-one(C22)

This compound was prepared as outlined above in procedures 1, 2, 3, and5 using commercially available intermediates4-methyl-1H-pyrrole-2-carbaldehyde and 5-bromo-7-chloroindolin-2-one.

¹H NMR (400 MHz, Methanol-d4) δ 7.61 (s, 1H), 7.43 (d, J=1.5 Hz, 1H),7.40 (s, 1H), 7.12-7.03 (m, 2H), 6.68 (s, 1H), 4.48 (t, J=4.4 Hz, 2H),3.54 (t, J=4.5 Hz, 2H), 2.14 (d, J=2.6 Hz, 3H). LCMS-ESI⁺ (m/z): [M+H]⁺calcd for C₂₂H₂₀ClN₄O₂: 407.1; found: 407.9.

Example 23:(Z)-3-((1H-pyrrol-2-yl)methylene)-7-chloro-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)indolin-2-one(C23)

This compound was prepared as outlined above in procedures 1, 2, 3, and5 using commercially available intermediate5-bromo-7-chloroindolin-2-one.

¹H NMR (400 MHz, Methanol-d4) δ 7.71 (s, 1H), 7.47 (d, J=1.5 Hz, 1H),7.42 (s, 1H), 7.30 (d, J=3.5 Hz, 1H), 7.11 (d, J=1.4 Hz, 1H), 6.87 (dt,J=3.7, 1.8 Hz, 1H), 6.39 (dt, J=3.7, 2.3 Hz, 1H), 4.55-4.46 (m, 2H),3.56 (t, J=4.5 Hz, 2H), 2.16 (s, 3H). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₂₁H₁₈ClN₄O₂: 393.1; found: 393.8.

Example 24:(Z)-7-methyl-3-((4-methyl-1H-pyrrol-2-yl)methylene)-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)indolin-2-one(C24)

This compound was prepared as outlined above in procedures 1, 2, 3, and5 using commercially available intermediates4-methyl-1H-pyrrole-2-carbaldehyde and 5-bromo-7-methylindolin-2-one.

¹H NMR (400 MHz, Methanol-d4) δ 7.53 (s, 1H), 7.41 (s, 1H), 7.33 (s,1H), 7.05 (s, 1H), 6.91 (s, 1H), 6.62 (s, 1H), 4.56 (t, J=4.5 Hz, 2H),3.59 (t, J=4.5 Hz, 2H), 2.33 (s, 3H), 2.19 (s, 3H), 2.14 (s, 3H).LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₃H₂₃N₄O₂: 387.2; found: 387.5.

Example 25:(Z)-7-fluoro-3-((4-methyl-1H-pyrrol-2-yl)methylene)-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)indolin-2-one(C25)

This compound was prepared as outlined above in procedures 1, 2, 3, and5 using commercially available intermediates4-methyl-1H-pyrrole-2-carbaldehyde and 5-bromo-7-fluoroindolin-2-one.

¹H NMR (400 MHz, Methanol-d4) δ 7.61 (s, 1H), 7.43 (s, 1H), 7.34 (d,J=1.3 Hz, 1H), 7.09 (d, J=2.4 Hz, 1H), 6.92 (dd, J=10.7, 1.4 Hz, 1H),6.68 (s, 1H), 4.58-4.49 (m, 2H), 3.62-3.53 (m, 2H), 2.16 (d, J=13.2 Hz,6H). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₂H₂₀FN₄O₂: 391.2; found: 391.4.

Example 26:(Z)-3-((1H-pyrrol-2-yl)methylene)-7-fluoro-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)indolin-2-one(C26)

This compound was prepared as outlined above in procedures 1, 2, 3, and5 using commercially available intermediate5-bromo-7-fluoroindolin-2-one.

¹H NMR (400 MHz, Methanol-d4) δ 7.71 (s, 1H), 7.44 (s, 1H), 7.37 (d,J=1.4 Hz, 1H), 7.29 (d, J=3.2 Hz, 1H), 6.94 (dd, J=10.7, 1.4 Hz, 1H),6.87 (dt, J=3.7, 1.6 Hz, 1H), 6.39 (dt, J=3.7, 2.3 Hz, 1H), 4.54 (dd,J=4.9, 4.0 Hz, 2H), 3.61-3.52 (m, 2H), 2.18 (s, 3H). LCMS-ESI⁺ (m/z):[M+H]⁺ calcd for C₂₁H₁₈FN₄O₂: 377.1; found: 377.4.

Example 27:(Z)-3-((1H-1,2,3-triazol-5-yl)methylene)-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)indolin-2-one(C27)

This compound was prepared as outlined above in procedures 1, 2, 3, and5 using commercially available intermediate1H-1,2,3-triazole-5-carbaldehyde.

¹H NMR (400 MHz, DMSO-d6) δ 10.68 (s, 1H), 9.26-8.22 (br m, 3H) 7.59 (s,1H), 7.39 (s, 1H), 7.21 (d, J=7.9 Hz, 1H), 6.95 (d, J=8.0 Hz, 1H), 4.35(s, 2H), 3.41 (s, 2H), 2.06 (s, 3H). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₁₉H₁₇N₆O₂: 361.1; found: 361.1.

Example 28:(Z)-3-((4-methyl-H-pyrrol-2-yl)methylene)-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)indolin-2-one(C28)

This compound was prepared as outlined above in procedures 1, 2, 3, and5 using commercially available intermediate4-methyl-1H-pyrrole-2-carbaldehyde.

¹H NMR (400 MHz, Methanol-d4) δ 7.57 (s, 1H), 7.51 (d, J=1.6 Hz, 1H),7.44 (s, 1H), 7.08 (td, J=7.5, 7.1, 2.2 Hz, 2H), 7.01 (d, J=7.9 Hz, 1H),6.64 (s, 1H), 4.59 (t, J=4.5 Hz, 2H), 3.61 (t, J=4.5 Hz, 2H), 2.20 (s,3H), 2.14 (s, 3H). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₂H₂₁N₄O₂: 373.2;found: 373.4.

Example 29:(Z)-3-((1H-pyrrol-2-yl)methylene)-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)indolin-2-one(C29)

This compound was prepared as outlined above in procedures 1, 2, 3, and5.

¹H NMR (400 MHz, Methanol-d4) δ 7.67 (s, 1H), 7.57-7.52 (m, 1H), 7.45(s, 1H), 7.28-7.22 (m, 1H), 7.11 (dd, J=8.0, 1.7 Hz, 1H), 7.02 (dd,J=8.0, 0.5 Hz, 1H), 6.85-6.80 (m, 1H), 6.37 (dt, J=3.7, 2.3 Hz, 1H),4.65-4.56 (m, 2H), 3.67-3.58 (m, 2H), 2.22 (s, 3H). LCMS-ESI⁺ (m/z):[M+H]⁺ calcd for C₂₁H9N₄O₂: 359.1; found: 359.4.

Example 30:(Z)-3-((1H-pyrazol-5-yl)methylene)-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)indolin-2-one(C30)

This compound was prepared as outlined above in procedures 1, 2, 3, and5 using commercially available intermediate 1H-pyrazole-5-carbaldehyde.

¹H NMR (400 MHz, Methanol-d4) δ 7.75 (d, J=2.4 Hz, 1H), 7.63 (s, 1H),7.42 (s, 1H), 7.21 (dd, J=7.9, 1.8 Hz, 1H), 7.00 (d, J=8.0 Hz, 1H), 6.73(d, J=2.3 Hz, 1H), 4.52 (t, J=4.5 Hz, 2H), 3.57 (d, J=4.7 Hz, 2H), 2.18(s, 3H). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₁H₁₈N₅O₂: 360.1; found:360.4.

Example 31:(Z)-3-((1H-imidazol-2-yl)methylene)-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)indolin-2-one(C31)

This compound was prepared as outlined above in procedures 1, 2, 3, and5 using commercially available intermediate 1H-imidazole-2-carbaldehyde.

¹H NMR (400 MHz, Methanol-d4) δ 7.76 (s, 2H), 7.73 (d, J=1.6 Hz, 1H),7.69 (s, 1H), 7.46 (s, 1H), 7.37 (dd, J=8.0, 1.7 Hz, 1H), 7.11 (d, J=8.1Hz, 1H), 4.59 (dd, J=5.0, 3.9 Hz, 2H), 3.61 (t, J=4.5 Hz, 2H), 2.19 (s,3H). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₀H₁₈N₅O₂: 360.1; found: 360.4.

Example 32:(Z)-3-((1H-imidazol-5-yl)methylene)-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)indolin-2-one(C32)

This compound was prepared as outlined above in procedures 1, 2, 3, and5 using commercially available intermediate 1H-imidazole-5-carbaldehyde.

¹H NMR (400 MHz, Methanol-d4) δ 8.87 (s, 1H), 8.03 (d, J=1.3 Hz, 1H),7.82 (s, 1H), 7.65 (d, J=1.8 Hz, 1H), 7.41 (s, 1H), 7.27 (dd, J=8.1, 1.7Hz, 1H), 7.07 (d, J=8.0 Hz, 1H), 4.56-4.47 (m, 2H), 3.56 (t, J=4.5 Hz,2H), 2.15 (s, 3H). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₁H₁₈N₅O₂: 360.1;found: 360.4.

Example 33:(Z)-7′-(3-((1H-imidazol-2-yl)methylene)-2-oxoindolin-5-yl)-8′-methylspiro[cyclopropane-1,3′-pyrido[2,3-b][1,4]oxazin]-2′(1′H)-one(C33)

A. Preparation of ethyl1-((5-bromo-4-methyl-3-nitropyridin-2-yl)oxy)cyclopropane-1-carboxylate(20)

5-bromo-2-chloro-4-methyl-3-nitropyridine (0.5 g, 1.98 mmol) was weighedinto a microwave vial and dissolved in ethyl1-hydroxycyclopropane-1-carboxylate (6.0 eq). DBU (3.0 eq) was added,the vial was sealed, and the reaction was heated to 80° C. for 4 hours.The reaction was diluted with water (20 mL) and EtOAc (10 mL) andextracted multiple times with EtOAc (5×10 mL). Combined organicfractions were concentrated under reduced pressure and the crudematerial was purified by silica gel chromatography (MeOH/CH₂Cl₂) to giveethyl1-((5-bromo-4-methyl-3-nitropyridin-2-yl)oxy)cyclopropane-1-carboxylate(20). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₁₂H₁₃BrN₂O₅: 345.0; found:345.2.

B. Preparation of7′-bromo-8′-methylspiro[cyclopropane-1,3′-pyrido[2,3-b][1,4]oxazin]-2′(1′H)-one(21)

Ethyl1-((5-bromo-4-methyl-3-nitropyridin-2-yl)oxy)cyclopropane-1-carboxylate(20) (0.182 g, 0.527 mmol) was dissolved in ethanol (1.0 mL) and aceticacid (4.0 mL) in a round bottom flask under argon. Zinc powder (5.5 eq)was added and the reaction was heated to 80° C. overnight. The reactionwas concentrated to dryness under reduced pressure, dissolved in aminimal amount of MeOH, and filtered to remove solids. The filtrate wasconcentrated under reduce pressure and the crude material was purifiedby silica gel chromatography (Rf 0.6 in 10% MeOH CH₂Cl₂) to give7′-bromo-8′-methylspiro[cyclopropane-1,3′-pyrido[2,3-b][1,4]oxazin]-2′(1′H)-one(21). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₁₀H₉BrN₂O₂: 269.0; found:269.1.

C. Preparation of(Z)-7′-(3-((1H-imidazol-2-yl)methylene)-2-oxoindolin-5-yl)-8′-methylspiro[cyclopropane-1,3′-pyrido[2,3-b][1,4]oxazin]-2′(1′H)-one(Example 33)

This compound was prepared as outlined in procedures 1, 2, 3, and 5using7′-bromo-8′-methylspiro[cyclopropane-1,3′-pyrido[2,3-b][1,4]oxazin]-2′(1′H)-one(21).

¹H NMR (400 MHz, DMSO-d6) δ 11.52 (s, 1H), 10.67 (s, 1H), 7.90-7.68 (m,5H), 7.33 (dd, J=8.0, 1.7 Hz, 1H), 7.05 (d, J=8.0 Hz, 1H), 2.21 (s, 3H),1.39-1.20 (m, 4H). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₂H₁₈N₅O₃: 400.1;found: 400.1.

Example 34:(Z)-3-((2-cyclopropyl-1H-imidazol-5-yl)methylene)-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)indolin-2-one(C34)

This compound was prepared as outlined above in procedures 1, 2, 3, and5 using commercially available intermediate2-cyclopropyl-1H-imidazole-5-carbaldehyde.

¹H NMR (400 MHz, Methanol-d4) δ 7.94 (s, 1H), 7.71 (d, J=1.6 Hz, 1H),7.49 (d, J=1.4 Hz, 1H), 7.38 (d, J=1.6 Hz, 1H), 7.14 (dd, J=10.6, 1.4Hz, 1H), 4.58-4.49 (m, 2H), 3.63-3.52 (m, 2H), 2.47-2.37 (m, 1H), 2.17(s, 3H), 1.49-1.39 (m, 2H), 1.30-1.21 (m, 2H). LCMS-ESI⁺ (m/z): [M+H]⁺calcd for C₂₃H₂₂N₅O₂: 400.2; found: 400.5.

Example 35:(Z)-3-((2-cyclopropyl-1H-imidazol-5-yl)methylene)-7-fluoro-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)indolin-2-one(C35)

This compound was prepared as outlined above in procedures 1, 2, 3, and5 using commercially available intermediates2-cyclopropyl-1H-imidazole-5-carbaldehyde and5-bromo-7-fluoroindolin-2-one.

¹H NMR (400 MHz, Methanol-d4) δ 7.96 (s, 1H), 7.81 (s, 1H), 7.49 (d,J=1.4 Hz, 1H), 7.44 (s, 1H), 7.14 (dd, J=10.6, 1.4 Hz, 1H), 4.58-4.50(m, 2H), 3.62-3.53 (m, 2H), 2.47-2.38 (m, 1H), 2.17 (s, 3H), 1.49-1.39(m, 2H), 1.30-1.21 (m, 2H). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₂₃H₂₁FN₅O₂: 418.2; found: 418.4.

Example 36:(Z)-3-(1-(1H-imidazol-5-yl)propylidene)-5-(8-methyl-2,3-dihydro-H-pyrido[2,3-b][1,4]oxazin-7-yl)indolin-2-one(C36)

This compound was prepared as outline in procedures 4 and 5 usingcommercially available intermediate 1-(1H-imidazol-5-yl)propan-1-one.

¹H NMR (400 MHz, Methanol-d4) δ 8.98 (d, J=1.2 Hz, 1H), 8.20 (d, J=1.3Hz, 1H), 7.62 (d, J=1.5 Hz, 1H), 7.50 (s, 1H), 7.33 (dd, J=8.0, 1.5 Hz,1H), 7.12 (d, J=8.0 Hz, 1H), 4.62 (t, J=4.5 Hz, 2H), 3.63 (t, J=4.5 Hz,2H), 3.17 (d, J=7.6 Hz, 2H), 2.22 (s, 3H), 1.36 (t, J=7.5 Hz, 3H).LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₃H₂₂N₅O₂: 388.2; found: 388.2.

Example 37:(Z)-3-((1H-pyrrolo[2,3-c]pyridin-2-yl)methylene)-6-methyl-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)indolin-2-one(C37)

This compound was prepared as outlined above in procedures 1, 2, 3, and5 using commercially available intermediates5-bromo-6-methylindolin-2-one and1H-pyrrolo[2,3-c]pyridine-2-carbaldehyde.

¹H NMR (400 MHz, Methanol-d4) δ 9.27 (q, J=0.8 Hz, 1H), 8.22 (dd, J=6.5,0.8 Hz, 1H), 8.14 (dd, J=6.5, 0.8 Hz, 1H), 7.90 (s, 1H), 7.56 (s, 1H),7.39 (s, 1H), 7.34 (d, J=0.7 Hz, 1H), 6.97 (s, 1H), 4.59 (t, J=4.5 Hz,2H), 3.62 (td, J=4.2, 2.0 Hz, 2H), 2.13 (s, 3H), 2.03 (s, 3H). LCMS-ESI⁺(m/z): [M+H]⁺ calcd for C₂₅H₂₂N₅O₂: 424.2; found: 424.1.

Example 38:(Z)-3-((1H-pyrrolo[3,2-b]pyridin-2-yl)methylene)-6-methyl-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)indolin-2-one(C38)

This compound was prepared as outlined above in procedures 1, 2, 3, and5 using commercially available intermediates5-bromo-6-methylindolin-2-one and1H-pyrrolo[3,2-b]pyridine-2-carbaldehyde.

¹H NMR (400 MHz, Methanol-d4) δ 8.72 (dt, J=8.3, 1.0 Hz, 1H), 8.61 (dd,J=5.8, 1.1 Hz, 1H), 7.87 (s, 1H), 7.74 (dd, J=8.3, 5.8 Hz, 1H), 7.54 (s,1H), 7.39 (s, 1H), 7.27 (d, J=0.8 Hz, 1H), 6.96 (s, 1H), 4.59 (t, J=4.5Hz, 2H), 3.62 (td, J=4.3, 2.3 Hz, 2H), 2.13 (s, 3H), 2.03 (s, 3H).LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₅H₂₂N₅O₂: 424.2; found: 424.1.

Example 39:(Z)-6-(3-((1H-pyrrolo[3,2-c]pyridin-2-yl)methylene)-2-oxoindolin-5-yl)-5-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one(C39)

This compound was prepared as outlined above in procedures 2, 3, and 5using commercially available intermediates5-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-benzo[b][1,4]oxazin-3(4H)-oneand 1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde.

¹H NMR (400 MHz, Methanol-d4) δ 8.68 (d, J=8.3 Hz, 1H), 8.59 (d, J=5.7Hz, 1H), 7.96 (s, 1H), 7.72 (dd, J=8.3, 5.7 Hz, 1H), 7.67 (d, J=1.4 Hz,1H), 7.29 (s, 1H), 7.26-7.19 (m, 1H), 7.02 (d, J=8.0 Hz, 1H), 6.90 (d,J=1.2 Hz, 2H), 4.56 (s, 2H), 2.65 (s, 1H), 2.19 (s, 3H). LCMS-ESI⁺(m/z): [M+H]⁺ calcd for C₂₅H₁₉N₄O₃: 423.1; found: 423.4.

Example 40:(Z)-3-((1H-pyrrolo[3,2-c]pyridin-2-yl)methylene)-6-methyl-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)indolin-2-one(C40)

This compound was prepared as outlined above in procedures 1, 2, 3, and5 using commercially available intermediates5-bromo-6-methylindolin-2-one and1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde.

¹H NMR (400 MHz, Methanol-d4) δ 9.21 (d, J=0.9 Hz, 1H), 8.40 (dd, J=6.8,0.9 Hz, 1H), 8.13 (dt, J=6.8, 0.9 Hz, 1H), 7.85 (s, 1H), 7.50 (d, J=3.1Hz, 2H), 7.35 (s, 1H), 6.95 (s, 1H), 4.54 (t, J=4.5 Hz, 2H), 3.59 (q,J=4.2 Hz, 2H), 2.12 (s, 3H), 2.00 (s, 3H). LCMS-ESI⁺ (m/z): [M+H]⁺ calcdfor C₂₅H₂₂N₅O₂: 424.2; found: 424.1.

Example 41:(Z)-3-((1H-pyrrolo[3,2-c]pyridin-2-yl)methylene)-5-(2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-6-methylindolin-2-one(C41)

This compound was prepared as outlined above in procedures 2, 3, and 5using commercially available intermediates(2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)boronic acid and1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde.

¹H NMR (400 MHz, Methanol-d4) δ 9.20 (s, 1H), 8.39 (dd, J=6.8, 0.9 Hz,1H), 8.12 (d, J=6.8 Hz, 1H), 7.87 (s, 1H), 7.57 (s, 1H), 7.51 (s, 1H),7.37 (d, J=2.1 Hz, 1H), 7.03 (d, J=2.2 Hz, 1H), 6.90 (s, 1H), 4.49-4.43(m, 2H), 3.47-3.42 (m, 3H), 2.30 (s, 4H). LCMS-ESI⁺ (m/z): [M+H]⁺ calcdfor C₂₄H₂₀N₅O₂: 410.2; found: 410.1.

Example 42:(Z)-3-((1H-pyrrolo[3,2-c]pyridin-2-yl)methylene)-5-(2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-7-fluoro-4-methylindolin-2-one(C42)

This compound was prepared as outlined above in procedures 2, 3, and 5using 7-fluoro-4-methylindolin-2-one (19) and commercially availableintermediates 1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and(2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)boronic acid.

¹H NMR (400 MHz, Methanol-d4) δ 9.25 (d, J=0.9 Hz, 1H), 8.41 (dd, J=6.7,0.9 Hz, 1H), 8.15 (dt, J=6.8, 0.9 Hz, 1H), 8.07 (s, 1H), 7.74-7.62 (m,1H), 7.37 (d, J=2.1 Hz, 1H), 7.07 (d, J=10.1 Hz, 1H), 7.05 (d, J=2.1 Hz,1H), 4.54-4.45 (m, 2H), 3.47 (d, J=4.2 Hz, 3H), 2.56 (s, 3H). LCMS-ESI⁺(m/z): [M+H]⁺ calcd for C₂₄H₁₉FN₅O₂: 428.1; found: 428.1.

Example 43:(Z)-3-((1H-pyrrolo[2,3-c]pyridin-2-yl)methylene)-6-fluoro-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)indolin-2-one(C43)

This compound was prepared as outlined above in procedures 1, 2, 3, and5 using commercially available intermediates5-bromo-6-fluoroindolin-2-one and1H-pyrrolo[2,3-c]pyridine-2-carbaldehyde.

¹H NMR (400 MHz, Methanol-d4) δ 9.26 (s, 1H), 8.23-8.12 (m, 2H), 7.97(s, 1H), 7.73 (d, J=7.0 Hz, 1H), 7.38 (d, J=11.9 Hz, 2H), 6.86 (d, J=9.4Hz, 1H), 4.45 (t, J=4.4 Hz, 2H), 3.52 (s, 2H), 2.05 (d, J=1.6 Hz, 3H).LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₄H9FN₅O₂: 428.1; found: 428.4.

Example 44:(Z)-3-((1H-pyrrolo[3,2-b]pyridin-2-yl)methylene)-6-fluoro-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)indolin-2-one(C44)

This compound was prepared as outlined above in procedures 1, 2, 3, and5 using commercially available intermediates5-bromo-6-fluoroindolin-2-one and1H-pyrrolo[3,2-b]pyridine-2-carbaldehyde.

¹H NMR (400 MHz, Methanol-d4) δ 8.69 (d, J=8.3 Hz, 1H), 8.62-8.56 (m,1H), 7.93 (s, 1H), 7.75-7.67 (m, 2H), 7.41 (s, 1H), 7.29 (s, 1H), 6.86(d, J=9.5 Hz, 1H), 4.47 (t, J=4.4 Hz, 2H), 3.53 (s, 2H), 2.06 (d, J=1.6Hz, 3H). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₄H₁₉FN₅O₂: 428.1; found:428.4.

Example 45:(Z)-3-((1H-pyrrolo[2,3-c]pyridin-2-yl)methylene)-7-fluoro-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)indolin-2-one(C45)

This compound was prepared as outlined above in procedures 1, 2, 3, and5 using commercially available intermediates5-bromo-7-fluoroindolin-2-one and1H-pyrrolo[2,3-c]pyridine-2-carbaldehyde.

¹H NMR (400 MHz, Methanol-d4) δ 9.29 (s, 1H), 8.25-8.14 (m, 2H), 8.09(s, 1H), 7.59 (s, 1H), 7.41 (d, J=2.7 Hz, 2H), 7.15 (d, J=10.5 Hz, 1H),4.45 (t, J=4.5 Hz, 2H), 3.57-3.49 (m, 2H), 2.14 (s, 3H). LCMS-ESI⁺(m/z): [M+H]⁺ calcd for C₂₄H₁₉FN₅O₂: 428.1; found: 428.4.

Example 46:(Z)-3-((1H-pyrrolo[3,2-b]pyridin-2-yl)methylene)-7-fluoro-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)indolin-2-one(C46)

This compound was prepared as outlined above in procedures 1, 2, 3, and5 using commercially available intermediates5-bromo-7-fluoroindolin-2-one and1H-pyrrolo[3,2-b]pyridine-2-carbaldehyde.

¹H NMR (400 MHz, Methanol-d4) δ 8.75-8.67 (m, 1H), 8.63 (dd, J=5.7, 1.1Hz, 1H), 8.06 (s, 1H), 7.75 (dd, J=8.3, 5.7 Hz, 1H), 7.58 (d, J=1.4 Hz,1H), 7.44 (s, 1H), 7.34 (d, J=0.9 Hz, 1H), 7.16 (dd, J=10.6, 1.4 Hz,1H), 4.56-4.45 (m, 2H), 3.61-3.49 (m, 2H), 2.16 (s, 3H). LCMS-ESI⁺(m/z): [M+H]⁺ calcd for C₂₄H₉FN₅O₂: 428.1; found: 428.4.

Example 47:(Z)-3-((1H-pyrrolo[3,2-c]pyridin-2-yl)methylene)-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one(C47)

This compound was prepared as outlined above in procedures 1, 2, 3, and5 using commercially available intermediates5-bromo-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one and1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde.

¹H NMR (400 MHz, Methanol-d4) δ 9.24 (s, 1H), 8.41 (d, J=6.7 Hz, 1H),8.16-8.01 (m, 4H), 7.59 (s, 1H), 7.37 (s, 1H), 4.38 (d, J=5.5 Hz, 2H),3.51-3.46 (m, 2H), 2.11 (s, 3H). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₂₃H9N₆O₂: 411.2; found: 411.4.

Example 48:(Z)-3-((1H-pyrrolo[3,2-c]pyridin-2-yl)methylene)-6-chloro-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)indolin-2-one(C48)

This compound was prepared as outlined above in procedures 1, 2, 3, and5 using commercially available intermediates5-bromo-6-chloroindolin-2-one and1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde.

¹H NMR (400 MHz, Methanol-d4) δ 9.23 (d, J=1.0 Hz, 1H), 8.40 (dd, J=6.8,0.9 Hz, 1H), 8.14 (d, J=6.8 Hz, 1H), 7.96 (s, 1H), 7.69 (s, 1H), 7.55(s, 1H), 7.37 (s, 1H), 7.15 (s, 1H), 4.51 (t, J=4.4 Hz, 2H), 3.55 (d,J=4.8 Hz, 2H), 2.02 (s, 3H). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₂₄H₁₉ClN₅O₂: 444.1; found: 444.9.

Example 49:(Z)-3-((1H-pyrrolo[3,2-c]pyridin-2-yl)methylene)-6-fluoro-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)indolin-2-one(C49)

This compound was prepared as outlined above in procedures 1, 2, 3, and5 using commercially available intermediates5-bromo-6-fluoroindolin-2-one and1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde.

¹H NMR (400 MHz, Methanol-d4) δ 9.22 (d, J=0.9 Hz, 1H), 8.40 (dd, J=6.8,0.9 Hz, 1H), 8.13 (dt, J=6.8, 0.9 Hz, 1H), 7.93 (s, 1H), 7.70 (d, J=7.0Hz, 1H), 7.54 (s, 1H), 7.44 (s, 1H), 6.87 (d, J=9.5 Hz, 1H), 4.51 (t,J=4.5 Hz, 2H), 3.56 (s, 2H), 2.08 (d, J=1.7 Hz, 3H). LCMS-ESI⁺ (m/z):[M+H]⁺ calcd for C₂₄H₁₉FN₅O₂: 428.1; found: 428.4.

Example 50:(Z)-3-((1H-indol-2-yl)methylene)-6-chloro-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)indolin-2-one(C50)

This compound was prepared as outlined above in procedures 1, 2, 3, and5 using commercially available intermediates5-bromo-6-chloroindolin-2-one and 1H-indole-2-carbaldehyde.

¹H NMR (400 MHz, Methanol-d4) δ 7.80 (d, J=1.6 Hz, 1H), 7.62 (d, J=8.9Hz, 2H), 7.51-7.42 (m, 2H), 7.29 (ddd, J=8.3, 6.9, 1.1 Hz, 1H),7.13-7.04 (m, 3H), 4.60 (t, J=4.5 Hz, 2H), 3.61 (q, J=4.2 Hz, 2H), 2.07(s, 3H). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₅H₂₀ClN₄O₂: 443.1; found:443.9.

Example 51:(Z)-3-((1H-indol-2-yl)methylene)-6-fluoro-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)indolin-2-one(C51)

This compound was prepared as outlined above in procedures 1, 2, 3, and5 using commercially available intermediates5-bromo-6-fluoroindolin-2-one and 1H-indole-2-carbaldehyde.

¹H NMR (400 MHz, Methanol-d4) δ 7.78 (s, 1H), 7.61 (t, J=7.8 Hz, 2H),7.50-7.43 (m, 2H), 7.28 (t, J=7.4 Hz, 1H), 7.10-7.03 (m, 2H), 6.83 (d,J=9.7 Hz, 1H), 4.55 (t, J=4.5 Hz, 2H), 3.62-3.53 (m, 2H), 2.11 (d, J=1.7Hz, 3H). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₅H₂₀FN₄O₂: 427.2; found:427.4.

Example 52:(Z)-3-((1H-pyrrolo[2,3-c]pyridin-2-yl)methylene)-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)indolin-2-one(C52)

This compound was prepared as outlined above in procedures 1, 2, 3, and5 using commercially available intermediates5-bromo-7-fluoroindolin-2-one and1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde.

¹H NMR (400 MHz, Methanol-d4) δ 9.24 (s, 1H), 8.41 (d, J=6.9 Hz, 1H),8.14 (d, J=6.8 Hz, 1H), 8.05 (s, 1H), 7.61-7.52 (m, 2H), 7.43 (s, 1H),7.13 (d, J=10.6 Hz, 1H), 4.49 (t, J=4.5 Hz, 2H), 3.55 (t, J=4.5 Hz, 2H),2.16 (s, 3H). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₄H₁₉FN₅O₂: 428.1;found: 428.4.

Example 53:(Z)-3-((1H-indol-2-yl)methylene)-7-fluoro-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)indolin-2-one(C53)

This compound was prepared as outlined above in procedures 1, 2, 3, and5 using commercially available intermediates5-bromo-7-fluoroindolin-2-one and 1H-indole-2-carbaldehyde.

¹H NMR (400 MHz, Methanol-d4) δ 7.88 (s, 1H), 7.63 (d, J=8.2 Hz, 1H),7.47 (dd, J=12.0, 7.8 Hz, 3H), 7.33-7.27 (m, 1H), 7.12-6.99 (m, 3H),4.52 (t, J=4.5 Hz, 2H), 3.57 (t, J=4.4 Hz, 2H), 2.18 (s, 3H). LCMS-ESI⁺(m/z): [M+H]⁺ calcd for C₂H₂₀FN₄O₂: 427.2; found: 427.4.

Example 54:(Z)-3-((1H-pyrrolo[3,2-c]pyridin-2-yl)methylene)-7-fluoro-4-methyl-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)indolin-2-one(C54)

This compound was prepared as outlined above in procedures 1, 2, 3, and5 using 7-fluoro-4-methylindolin-2-one (19) and commercially availableintermediate 1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde.

¹H NMR (400 MHz, Methanol-d4) δ 9.25 (d, J=0.8 Hz, 1H), 8.42 (dd, J=6.8,0.9 Hz, 1H), 8.15 (dt, J=6.8, 0.9 Hz, 1H), 8.07 (s, 1H), 7.70 (d, J=0.9Hz, 1H), 7.42 (s, 1H), 7.04 (d, J=9.9 Hz, 1H), 4.63 (t, J=4.5 Hz, 2H),3.64 (td, J=4.3, 2.4 Hz, 2H), 2.41 (s, 3H), 2.05 (s, 3H). LCMS-ESI⁺(m/z): [M+H]⁺ calcd for C₂₅H₂₁FN₅O₂: 442.2; found: 442.1.

Example 55:(Z)-3-((1H-indol-2-yl)methylene)-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one(C55)

This compound was prepared as outlined above in procedures 1, 2, 3, and5 using commercially available intermediates5-bromo-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one and1H-indole-2-carbaldehyde.

¹H NMR (400 MHz, Methanol-d4) δ 8.02 (d, J=14.7 Hz, 2H), 7.93 (s, 1H),7.64 (d, J=7.9 Hz, 1H), 7.57-7.45 (m, 2H), 7.31 (t, J=7.4 Hz, 1H),7.17-7.05 (m, 2H), 4.64 (d, J=5.4 Hz, 2H), 3.64 (s, 2H), 2.24 (s, 3H).LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₄H₂₀N₅O₂: 410.2; found: 410.4.

Example 56:(Z)-3-((1H-indol-2-yl)methylene)-7-fluoro-4-methyl-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)indolin-2-one(C56)

This compound was prepared as outlined above in procedures 1, 2, 3, and5 using 7-fluoro-4-methylindolin-2-one (19) and commercially availableintermediate 1H-indole-2-carbaldehyde.

¹H NMR (400 MHz, Methanol-d4) δ 13.07 (s, 1H), 8.00 (d, J=1.6 Hz, 1H),7.63 (d, J=8.1 Hz, 1H), 7.49 (dd, J=8.4, 1.0 Hz, 1H), 7.41 (s, 1H), 7.30(ddd, J=8.2, 7.0, 1.1 Hz, 1H), 7.14 (d, J=1.1 Hz, 1H), 7.08 (ddd, J=8.1,6.9, 1.0 Hz, 1H), 6.90 (d, J=10.0 Hz, 1H), 4.63 (t, J=4.6 Hz, 2H),3.72-3.55 (m, 2H), 2.37 (s, 3H), 2.05 (s, 3H). LCMS-ESI⁺ (m/z): [M+H]⁺calcd for C₂₆H₂₂FN₄O₂: 441.2; found: 441.1.

Example 57:(Z)-3-((1H-pyrrolo[3,2-b]pyridin-2-yl)methylene)-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)indolin-2-one(C57)

This compound was prepared as outlined above in procedures 1, 2, 3, and5 using commercially available intermediate1H-pyrrolo[3,2-b]pyridine-2-carbaldehyde.

¹H NMR (400 MHz, Methanol-d4) δ 8.69 (d, J=8.3 Hz, 1H), 8.60 (dd, J=5.7,1.1 Hz, 1H), 8.00 (s, 1H), 7.76-7.69 (m, 2H), 7.41 (s, 1H), 7.29 (dd,J=8.1, 1.4 Hz, 2H), 7.06 (d, J=8.0 Hz, 1H), 4.49 (t, J=4.5 Hz, 2H),3.60-3.50 (m, 2H), 2.15 (s, 3H). LCMS-ESI+(m/z): [M+H]⁺ calcd forC₂₄H₂₀N₅O₂: 410.2; found: 410.4.

Example 58:(Z)-3-((1H-pyrrolo[2,3-c]pyridin-2-yl)methylene)-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)indolin-2-one(C58)

This compound was prepared as outlined above in procedures 1, 2, 3, and5 using commercially available intermediate1H-pyrrolo[2,3-c]pyridine-2-carbaldehyde.

¹H NMR (400 MHz, Methanol-d4) δ 9.28 (q, J=0.9 Hz, 1H), 8.19 (ddd,J=29.8, 6.5, 0.8 Hz, 2H), 8.04 (s, 1H), 7.77 (d, J=1.6 Hz, 1H), 7.44 (s,1H), 7.38 (d, J=0.8 Hz, 1H), 7.31 (dd, J=8.0, 1.7 Hz, 1H), 7.08 (d,J=7.9 Hz, 1H), 4.58-4.48 (m, 2H), 3.63-3.51 (m, 2H), 2.18 (s, 3H).LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₄N₂₀N₅O₂: 410.2; found: 410.4.

Example 59:(Z)-3-((1H-benzo[d]imidazol-2-yl)methylene)-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)indolin-2-one(C59)

This compound was prepared as outlined above in procedures 1, 2, 3, and5 using commercially available intermediate1H-benzo[d]imidazole-2-carbaldehyde.

¹H NMR (400 MHz, Methanol-d4) δ 7.86-7.72 (m, 4H), 7.51 (dd, J=6.3, 3.2Hz, 2H), 7.46 (s, 1H), 7.34 (dd, J=8.0, 1.7 Hz, 1H), 7.09 (d, J=8.0 Hz,1H), 4.56 (t, J=4.5 Hz, 2H), 3.60 (t, J=4.4 Hz, 2H), 2.19 (s, 3H).LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₄H₂₀N₅O₂: 410.2; found: 410.4.

Example 60:(Z)-3-((1H-pyrrolo[3,2-c]pyridin-2-yl)methylene)-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)indolin-2-one(C60)

This compound was prepared as outlined above in procedures 1, 2, 3, and5 using commercially available intermediate1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde.

¹H NMR (400 MHz, Methanol-d4) δ 9.22 (d, J=0.9 Hz, 1H), 8.40 (dd, J=6.8,0.9 Hz, 1H), 8.13 (d, J=6.8 Hz, 1H), 7.98 (s, 1H), 7.72 (s, 1H), 7.55(s, 1H), 7.44 (d, J=3.1 Hz, 1H), 7.28 (d, J=8.1 Hz, 1H), 7.07 (d, J=8.0Hz, 1H), 4.55 (t, J=4.7 Hz, 2H), 3.59 (t, J=4.4 Hz, 2H), 2.18 (d, J=2.7Hz, 3H). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₄H₂₀N₅O₂: 410.2; found:410.4.

Example 61:(Z)-3-((1H-pyrrolo[2,3-b]pyridin-2-yl)methylene)-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)indolin-2-one(C61)

This compound was prepared as outlined above in procedures 1, 2, 3, and5 using commercially available intermediate1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde.

¹H NMR (400 MHz, Methanol-d4) δ 8.38 (dd, J=5.0, 1.6 Hz, 1H), 8.21 (dd,J=8.0, 1.5 Hz, 1H), 7.87 (s, 1H), 7.68 (d, J=1.7 Hz, 1H), 7.48 (s, 1H),7.28-7.19 (m, 2H), 7.12 (s, 1H), 7.05 (d, J=8.0 Hz, 1H), 4.62 (t, J=4.5Hz, 2H), 3.66-3.59 (m, 2H), 2.23 (s, 3H). LCMS-ESI⁺ (m/z): [M+H]⁺ calcdfor C₂H₂₀N₅O₂: 410.2; found: 410.4.

Example 62:(Z)-3-((1H-indol-2-yl)methylene)-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)indolin-2-one(C62)

This compound was prepared as outlined above in procedures 1, 2, 3, and5 using commercially available intermediate 1H-indole-2-carbaldehyde.

¹H NMR (400 MHz, Methanol-d4) δ 7.82 (s, 1H), 7.65-7.58 (m, 2H), 7.47(d, J=8.3 Hz, 1H), 7.41 (s, 1H), 7.27 (t, J=7.6 Hz, 1H), 7.15 (d, J=8.0Hz, 1H), 7.10-6.99 (m, 3H), 4.49 (t, J=4.6 Hz, 2H), 3.59-3.51 (m, 2H),2.16 (s, 3H). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₅H₂₁N₄O₂: 409.2;found: 409.5.

Example 63:(Z)-3-((1H-pyrrolo[2,3-c]pyridin-2-yl)methylene)-7-fluoro-4-methyl-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)indolin-2-one(C63)

This compound was prepared as outlined above in procedures 1, 2, 3, and5 using 7-fluoro-4-methylindolin-2-one (19) and commercially availableintermediate 1H-pyrrolo[2,3-c]pyridine-2-carbaldehyde.

¹H NMR (400 MHz, Methanol-d4) δ 9.31 (q, J=0.8 Hz, 1H), 8.24 (dd, J=6.5,0.8 Hz, 1H), 8.17 (dd, J=6.5, 0.8 Hz, 1H), 8.09 (s, 1H), 7.51 (d, J=0.8Hz, 1H), 7.37 (s, 1H), 7.06 (d, J=9.9 Hz, 1H), 4.56 (t, J=4.5 Hz, 2H),3.60 (td, J=4.3, 2.2 Hz, 2H), 2.42 (s, 3H), 2.01 (s, 3H). LCMS-ESI⁺(m/z): [M+H]⁺ calcd for C₂₅H₂₁FN₅O₂: 442.2; found: 442.1.

Example 64:(Z)-3-((1H-pyrrolo[3,2-b]pyridin-2-yl)methylene)-7-fluoro-4-methyl-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)indolin-2-one(C64)

This compound was prepared as outlined above in procedures 1, 2, 3, and5 using 7-fluoro-4-methylindolin-2-one (19) and commercially availableintermediate 1H-pyrrolo[3,2-b]pyridine-2-carbaldehyde.

¹H NMR (400 MHz, Methanol-d4) δ 8.76 (dt, J=8.5, 1.0 Hz, 1H), 8.64 (dd,J=5.7, 1.1 Hz, 1H), 8.08 (s, 1H), 7.77 (dd, J=8.4, 5.7 Hz, 1H), 7.48 (d,J=0.9 Hz, 1H), 7.39 (s, 1H), 7.06 (d, J=9.9 Hz, 1H), 4.66-4.51 (m, 2H),3.62 (td, J=4.3, 2.0 Hz, 2H), 2.41 (s, 3H), 2.03 (s, 3H). LCMS-ESI⁺(m/z): [M+H]⁺ calcd for C₂₅H₂₁FN₅O₂: 442.2; found: 442.1.

Example 65:(Z)-3-((1H-pyrazol-4-yl)methylene)-7-fluoro-4-methyl-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)indolin-2-one(C65)

This compound was prepared as outlined above in procedures 1, 2, 3, and5 using 7-fluoro-4-methylindolin-2-one (19) and commercially availableintermediate 1H-pyrazole-4-carbaldehyde.

¹H NMR (400 MHz, Methanol-d4) δ 8.65 (s, 2H), 7.95 (s, 1H), 7.40 (s,1H), 6.89 (d, J=10.0 Hz, 1H), 4.62 (q, J=6.2, 5.4 Hz, 2H), 3.63 (td,J=4.4, 2.6 Hz, 2H), 2.33 (s, 3H), 2.04 (s, 3H). LCMS-ESI⁺ (m/z): [M+H]⁺calcd for C₂₁H₁₉FN₅O₂: 392.1; found: 392.1.

Example 66:(Z)-3-((1H-pyrazol-4-yl)methylene)-7-chloro-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)indolin-2-one(C66)

This compound was prepared as outlined above in procedures 1, 2, 3, and5 using commercially available intermediates 1H-pyrazole-4-carbaldehydeand 5-bromo-7-chloroindolin-2-one.

¹H NMR (400 MHz, Methanol-d4) δ 8.64 (s, 2H), 7.83 (s, 1H), 7.52 (d,J=1.5 Hz, 1H), 7.44 (s, 1H), 7.18 (d, J=1.5 Hz, 1H), 4.55 (t, J=4.4 Hz,2H), 3.59 (t, J=4.5 Hz, 2H), 2.18 (s, 3H). LCMS-ESI⁺ (m/z): [M+H]⁺ calcdfor C₂₀H₁₇ClN₅O₂: 394.1; found: 394.8.

Example 67:(Z)-3-((1H-pyrazol-4-yl)methylene)-7-methyl-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)indolin-2-one(C67)

This compound was prepared as outlined above in procedures 1, 2, 3, and5 using commercially available intermediates 1H-pyrazole-4-carbaldehydeand 5-bromo-7-mrthylindolin-2-one.

¹H NMR (400 MHz, Methanol-d4) δ 8.62 (s, 2H), 7.74 (s, 1H), 7.42 (d,J=11.7 Hz, 2H), 6.98 (s, 1H), 4.60 (t, J=4.5 Hz, 2H), 3.62 (t, J=4.5 Hz,2H), 2.33 (s, 3H), 2.21 (s, 3H). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₂₁H₂₀N₅O₂: 374.2; found: 374.4.

Example 68:(Z)-3-((3-methyl-H-pyrazol-4-yl)methylene)-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)indolin-2-one(C68)

This compound was prepared as outlined above in procedures 1, 2, 3, and5 using commercially available intermediate3-methyl-1H-pyrazole-4-carbaldehyde.

¹H NMR (400 MHz, Methanol-d4) δ 9.20 (s, 1H), 7.64 (dd, J=2.4, 0.8 Hz,2H), 7.48 (s, 1H), 7.14 (dd, J=8.0, 1.7 Hz, 1H), 7.03-6.95 (m, 1H), 4.63(dd, J=5.0, 3.9 Hz, 2H), 3.64 (dd, J=5.1, 4.0 Hz, 2H), 2.48 (s, 3H),2.23 (s, 3H). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₁H₂₀H₅O₂: 374.2;found: 374.4.

Example 69:(Z)-3-((1H-pyrazol-4-yl)methylene)-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)indolin-2-one(C69)

This compound was prepared as outlined above in procedures 1, 2, 3, and5 using commercially available intermediate 1H-pyrazole-4-carbaldehyde.

¹H NMR (400 MHz, Methanol-d4) δ 8.61 (s, 2H), 7.77 (s, 1H), 7.57 (d,J=1.6 Hz, 1H), 7.43 (s, 1H), 7.14 (dd, J=8.0, 1.7 Hz, 1H), 6.99 (d,J=8.0 Hz, 1H), 4.62-4.50 (m, 2H), 3.60 (t, J=4.5 Hz, 2H), 2.19 (s, 3H).LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₀H₁₈N₅O₂: 360.1; found: 360.4.

Example 70:(Z)-3-((1H-indol-3-yl)methylene)-5-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)indolin-2-one(C70)

This compound was prepared as outlined above in procedures 1, 2, 3, and5 using commercially available intermediate 1H-indole-3-carbaldehyde.

¹H NMR (400 MHz, Methanol-d4) δ 9.44 (s, 1H), 8.21 (s, 1H), 8.14 (s,1H), 8.04-7.96 (m, 2H), 7.72 (d, J=1.6 Hz, 1H), 7.61 (d, J=7.8 Hz, 1H),7.53-7.44 (m, 3H), 7.36 (s, 1H), 4.53 (t, J=4.5 Hz, 2H), 3.56 (t, J=4.4Hz, 2H), 2.12 (s, 3H). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₅H₂₁N₄O₂:409.2; found: 409.5.

Example 71:(Z)-3-((1H-imidazol-2-yl)methylene)-5-(2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)indolin-2-one(C71)

This compound was prepared as outlined above in procedures 2, 3, and 5using commercially available intermediate 1H-imidazole-2-carbaldehydeand7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine.

¹H NMR (400 MHz, DMSO-d6) δ 11.44 (s, 1H), 8.06 (d, J=1.7 Hz, 1H), 7.89(s, 1H), 7.77-7.68 (m, 3H), 7.52 (dd, J=8.1, 1.8 Hz, 1H), 7.19 (d, J=2.3Hz, 1H), 7.02 (d, J=8.1 Hz, 1H), 4.32 (dd, J=5.2, 3.6 Hz, 2H), 3.33 (d,J=8.9 Hz, 2H). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C19H15N5O2: 346.1;found: 346.1.

Example 72:((Z)-3-((1H-imidazol-2-yl)methylene)-5-(8′-methyl-1′,2′-dihydrospiro[cyclopropane-1,3′-pyrido[2,3-b][1,4]oxazin]-7′-yl)indolin-2-one(C72)

A. Preparation of7′-bromo-8′-methyl-1′,2′-dihydrospiro[cyclopropane-1,3′-pyrido[2,3-b][1,4]oxazine]((22)

7′-bromo-8′-methylspiro[cyclopropane-1,3′-pyrido[2,3-b][1,4]oxazin]-2′(1′H)-one(260 mg, 0.966 mmol) (21) was dissolved in THF (2.0 mL) under argon andborane-THF (4 equiv.) was added. The reaction was heated to 90° C. for24 hrs. Another 4 equiv. of borane-THF was added and the reaction washeated to 90° C. for another 24 hours. The reaction was cooled to roomtemperature, quenched with a 1:1 MeOH/water mixture (1 mL), concentratedunder reduced pressure, dry loaded on to silica gel, and purified bysilica gel chromatography (Rf 0.4 in 5% MeOH/CH2C₂) to give7′-bromo-8′-methyl-1′,2′-dihydrospiro[cyclopropane-1,3′-pyrido[2,3-b][1,4]oxazine](22). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₁₀H₁₁BrN₂O: 255.1; found:255.1.

B. Preparation of(Z)-3-((1H-imidazol-2-yl)methylene)-5-(8′-methyl-1′,2′-dihydrospiro[cyclopropane-1,3′-pyrido[2,3-b][1,4]oxazin]-7′-yl)indolin-2-one(C72)

This compound was prepared as outlined in procedures 1, 2, 3, and 5using7′-bromo-8′-methyl-1′,2′-dihydrospiro[cyclopropane-1,3′-pyrido[2,3-b][1,4]oxazine](22).

¹H NMR (400 MHz, DMSO-d6) δ 11.54 (s, 1H), 7.90-7.72 (m, 4H), 7.42-7.27(m, 2H), 7.04 (d, J=8.0 Hz, 1H), 3.34 (s, 2H), 2.06 (s, 3H), 1.06-0.95(m, 2H), 0.86-0.73 (m, 2H). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₂₂H₁₈N₅O₃: 386.1; found: 386.1.

HPK1 IC₅₀ Assay

The enzymatic activity of human HPK1 (MAP4K1) was monitored in abiochemical assay in the presence or absence of compounds and using asynthetic peptide substrate. An increase in phosphorylation of thepeptide by HPK1 was indicative of its kinase activity.

Recombinant HPK1 kinase domain produced via baculovirus infection ofinsect cells was obtained from Proteros (Proteros Biostructures#PR-0322) and was pre-activated in the presence of 2 mM ATP(Sigma-Aldrich, cat #GE27-2056-01) and 2 mM magnesium chloride for 16hours at 4° C. The protein reaction mixture was then loaded to adesalting column (Thermo Fisher Scientific, Cat #89889) to remove excessATP. HPK1 was eluted with buffer containing 20 mM Tris(2-Amino-2-(hydroxymethyl)propane-1,3-diol) pH 8.0, 150 mM NaCl, 2 mMdithiothreitol and 5% glycerol, and was frozen at −80° C. for later use.HPK1 dual phosphorylation was confirmed by mass spectrometry.

Ten nanoliters of test compounds dissolved in DMSO at variousconcentrations were dispensed into a 384-well ProxiPlate (PerkinElmer#6008289). Five microliters of a solution of recombinant HPK1 diluted inHPK1 kinase assay buffer (50 mM BES[N,N-Bis(2-hydroxyethyl)-2-aminoethanesulfonic acid], pH 7.0; 10 mMmagnesium chloride; 0.01% Triton X-100; 1 mM dithiothreitol; 0.01%bovine serum albumin; 0.1 mM sodium orthovanadate) was added to thecompound-containing plate and was incubated for 15 minutes at 25° C.Five microliters of a mixture of ATP (Sigma-Aldrich #A6559) and peptidesubstrate STK Si (Cisbio #61ST1BLC) diluted in HPK1 kinase assay bufferwas then added to start the reaction. Final concentrations were 0.15 nMfor HPK1, 10 M for ATP, and 1 M for the STK S peptide substrate. Thereaction mixture was incubated at 25° C. for 3 hours and was stoppedwith the addition of 10 μl of an EDTA (Ethylenediaminetetraaceticacid)-containing detection buffer (Cisbio #62SDBRDF) supplemented withEuropium cryptate-labeled anti-phospho-serine/threonine antibodies(Cisbio #62ST1PEJ) and XL665-labeled streptavidin (Cisbio #610SAXLG).The mixture was incubated for 16 hours at room temperature and peptidephosphorylation was measured by time-resolved fluorescence energytransfer (665 nm/620 nm) on an Envision plate reader (PerkinElmer).

Data in Table 1 were normalized based on positive (staurosporine) andnegative (DMSO) controls. Least squares curve fittings were performedusing a four-parameter variable slope nonlinear regression model. IC₅₀is defined as the concentration of compound required to inhibit 50% ofmaximum phosphorylation. IC₅₀ values from multiple experiments wereaveraged by geometric mean and the standard deviation was calculated.

TABLE 1 Compound No. HPK1 IC₅₀ (nM) C1 0.05 C2 1.95 C3 0.19 C4 0.15 C57.43 C6 0.12 C7 0.29 C8 0.18 C9 0.09 C10 0.22 C11 0.44 C12 0.67 C13 0.51C14 0.29 C15 0.07 C16 0.05 C17 0.05 C18 3.02 C19 1.88 C20 0.16 C21 0.07C22 2.61 C23 1.98 C24 2.93 C25 0.05 C26 0.05 C27 1.64 C28 0.05 C29 0.05C30 0.97 C31 0.77 C32 0.26 C33 5.66 C34 0.13 C35 0.05 C36 1.00 C37 0.69C38 0.11 C39 7.03 C40 0.07 C41 5.73 C42 9.30 C43 0.13 C44 0.05 C45 0.17C46 0.05 C47 1.13 C48 0.16 C49 0.16 C50 0.19 C51 0.16 C52 0.10 C53 0.16C54 0.27 C55 1.24 C56 0.51 C57 0.05 C58 0.11 C59 0.28 C60 0.06 C61 1.10C62 0.05 C63 0.41 C64 0.31 C65 1.03 C66 6.90 C67 4.33 C68 0.32 C69 0.26C70 0.42 C71 66.7 C72 2.13

All references, including publications, patents, and patent documentsare incorporated by reference herein, as though individuallyincorporated by reference. The present disclosure provides reference tovarious embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the present disclosure. The descriptionis made with the understanding that it is to be considered anexemplification of the claimed subject matter and is not intended tolimit the appended claims to the specific embodiments illustrated.

What is claimed:
 1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: A is N or CR¹;each R¹, R², and R³ is independently H, halogen, —CN, —N(R¹³)₂, C₁-C₃alkyl, C₁-C₃ haloalkyl, C₂-C₃ alkynyl, C₁-C₃ alkoxy, or —SO₂R¹³, whereinthe C₂-C₃ alkynyl is unsubstituted or substituted with 1, 2, or 3 R⁹groups; one of B and E is

and the other is J; J is H, —CN, C₁-C₃ alkyl, or C₃-C₆ cycloalkyl;wherein the C₁-C₃ alkyl or C₃-C₆ cycloalkyl is unsubstituted orsubstituted with 1, 2, or 3 R¹⁰ groups;

is a group of formula

wherein W is NR⁴ or S; X is N or CR⁵; Y is N or CR⁶; Z is N or CR⁷; X¹is NH; R⁴ is H; each R⁵, R⁶, and R⁷ is independently H, halogen, —CN,—CON(R⁸)₂, —NR¹³C(O)R¹³, —SO₂N(R¹³)₂, C₁-C₃ alkyl, C₁-C₃ alkoxy,—N(R¹³)₂, C₃-C₆ cycloalkyl, C₆-C₁₀ aryl, 5-10 membered heteroaryl having1, 2, or 3 heteroatoms independently selected from N, O, and S, and 4-6membered heterocyclyl having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S; wherein the C₁-C₃ alkyl, C₁-C₃ alkoxy, C₃-C₆cycloalkyl, C₆-C₁₀ aryl, 5-10 membered heteroaryl, or 4-6 memberedheterocyclyl is unsubstituted or substituted with 1, 2, or 3 R¹¹ groups;or wherein R⁵ and R⁶, or R⁶ and R⁷ together with atoms to which they areattached form a phenyl or a 5-6 membered heteroaryl having 1 or 2heteroatoms independently selected from N, O, and S; wherein the phenylor the 5-6 membered heteroaryl is unsubstituted or substituted with 1,2, or 3 R¹¹ groups; each R⁸ is independently H or C₁-C₃ alkyl, whereinthe C₁-C₃ alkyl is unsubstituted or substituted with 1, 2, or 3R¹²groups; or wherein two R⁸ groups together with the nitrogen they areattached to form a 4-6 membered heterocyclic ring having 1 or 2heteroatoms selected from the group consisting of N, O, or S, whereinthe 4-6 membered heterocyclic ring is unsubstituted or substituted with1, 2, or 3 R¹² groups; each R⁹ is independently —OR¹³, C₁-C₃ alkyl, orC₃-C₆ cycloalkyl; each R¹⁰ and R¹¹ is independently selected from thegroup consisting of —OR¹³, halogen, CN, —N(R⁸)₂, —CON(R⁸)₂,—N(R¹³)COR¹³, —S(O)₂R¹³, C₁-C₃ alkyl, C₃-C₆ cycloalkyl, 4-6 memberedheterocyclyl having 1, 2, or 3 heteroatoms independently selected fromN, O, and S, C₆-C₁₀ aryl, and 5-10 membered heteroaryl having 1, 2, or 3heteroatoms independently selected from N, O, and S; each R¹² isindependently —OR¹³, C₁-C₃ alkyl, or —N(R¹³)₂; wherein the C₁-C₃ alkylis unsubstituted or substituted with 1, 2, or 3 groups independentlyselected from —OR¹³ and —N(R¹³)₂; each R¹³ is independently H or C₁-C₃alkyl, wherein the C₁-C₃ alkyl is unsubstituted or substituted with 1,2, or 3 R²²groups; each R²² is independently selected from the groupconsisting of halogen, —OH, C₁-C₃ alkyl, C₁-C₃ alkoxy, —NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃ alkyl)₂ wherein each C₁-C₃ alkyl is same or different,C₃-C₆ cycloalkyl, 4-6 membered heterocyclyl with 1, 2, or 3 heteroatomsselected from N, O, and S, C₆-C₁₀ aryl, and 5-10 membered heteroarylhaving 1, 2, or 3 heteroatoms independently selected from N, O, and S;and

is a group of formula:

wherein L¹ is N or CR¹⁹; n is 0, 1 or 2; m is 0, 1, or 2; p is 0, 1, 2,3, 4, 5, or 6; R¹⁹ is H, —OR¹³, halogen, CN, —N(R¹³)₂, or C₁-C₃ alkyl;each R²⁰ is independently —OR¹³, halogen, CN, —N(R¹³)₂, or C₁-C₃ alkyl;and each R²¹ is independently —OR¹³, oxo, halogen, CN, —N(R¹³)₂, orC₁-C₃ alkyl; or two R²¹ groups on same or adjoining atoms are joinedtogether to form a 3-6 membered carbocyclic ring or a 3-6 memberedheterocyclic ring having 1 or 2 heteroatoms selected from N, O, and S.2. The compound of claim 1, or the pharmaceutically acceptable saltthereof, wherein the compound is of a Formula I-Z:


3. The compound of claim 1, or the pharmaceutically acceptable saltthereof, wherein the compound is of a Formula I-E:


4. The compound of claim 1, or the pharmaceutically acceptable saltthereof, wherein


5. The compound of claim 1, or the pharmaceutically acceptable saltthereof, wherein


6. The compound of claim 1, or the pharmaceutically acceptable saltthereof, wherein


7. The compound of claim 1, or the pharmaceutically acceptable saltthereof, wherein the compound is of a Formula II-Z:


8. The compound of claim 1, or the pharmaceutically acceptable saltthereof, wherein the compound is of a Formula IIa-Z:


9. The compound of claim 1, or the pharmaceutically acceptable saltthereof, wherein each R⁵, R⁶, and R⁷ is independently H, halogen, —CN,—CON(R⁸)₂, —NR¹³C(O)R¹³, —SO₂N(R¹³)₂, C₁-C₃ alkyl, 5-6 memberedheteroaryl having 1 or 2 heteroatoms independently selected from N, Oand S, or C₃-C₆ cycloalkyl; wherein the C₁-C₃ alkyl or the C₃-C₆cycloalkyl is unsubstituted or substituted with 1, 2, or 3 R¹¹ groups.10. The compound of claim 1, or the pharmaceutically acceptable saltthereof, wherein R⁵ is H, C₁-C₃ alkyl, or C₃-C₆ cycloalkyl.
 11. Thecompound of claim 1, or the pharmaceutically acceptable salt thereof,wherein R⁶ is H, halogen, CN, C₁-C₃ alkyl, or CON(R⁸)₂.
 12. The compoundof claim 1, or the pharmaceutically acceptable salt thereof, wherein R⁷is H or C₁-C₃ alkyl.
 13. The compound of claim 1, or thepharmaceutically acceptable salt thereof, wherein each R⁵, R⁶, and R⁷ isH.
 14. The compound of claim 1, or the pharmaceutically acceptable saltthereof, wherein: X is CR⁵; Y is CR⁶, and wherein R⁵ and R⁶ togetherwith atoms to which they are attached form a phenyl or 5-6 memberedheteroaryl having 1 or 2 heteroatoms independently selected from N, O,and S; wherein the phenyl or the 5-6 membered heteroaryl isunsubstituted or substituted with 1, 2, or 3 R¹¹ groups.
 15. Thecompound of claim 1, or the pharmaceutically acceptable salt thereof,wherein Y is CR⁶; Z is CR⁷, and wherein R⁶ and R⁷ together with atoms towhich they are attached form a phenyl or 5-6 membered heteroaryl having1 or 2 heteroatoms independently selected from N, O, and S; wherein thephenyl or the 5-6 membered heteroaryl is unsubstituted or substitutedwith 1, 2, or 3 R¹¹ groups.
 16. The compound of claim 1, or thepharmaceutically acceptable salt thereof, wherein R¹¹ is selected fromthe group consisting of (i) CN, (ii) —N(R⁸)₂, (iii) —N(R¹³)COR¹³, and(iv) 4-6 membered heterocyclyl having 1, 2, or 3, heteroatomsindependently selected from N, O, and S; wherein each R¹³ isindependently H or C₁-C₃ alkyl, wherein the C₁-C₃ alkyl is unsubstitutedor substituted with 1, 2, or 3 R²² groups; and each R²² is independentlyselected from the group consisting of halogen, —OH, C₁-C₃ alkyl, C₁-C₃alkoxy, —NH₂, —NH(C₁-C₃ alkyl), —N(C₁-C₃ alkyl)₂ wherein each C₁-C₃alkyl is same or different, C₃-C₆ cycloalkyl, 4-6 membered heterocyclylwith 1, 2, or 3 heteroatoms selected from N, O, and S, C₆-C₁₀ aryl, and5-10 membered heteroaryl having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S.
 17. The compound of a claim 1, or thepharmaceutically acceptable salt thereof, wherein R¹¹ is selected fromthe group consisting of (i) —CN, (ii) —NH₂, (iii) —NHCOR¹³, and (iv) 6membered heterocyclyl having 1 or 2 heteroatoms independently selectedfrom N and O; wherein R¹³ is C₁-C₃ alkyl.
 18. The compound of claim 1,or the pharmaceutically acceptable salt thereof, wherein the compoundhas a Formula IIb-Z:

wherein L is N or CR¹⁵; M is N or CR¹⁶; Q is N or CR¹⁷; and R is N orCR¹⁸; wherein each R¹⁵, R¹⁶, R¹⁷, and R¹⁸ is independently selected fromthe group consisting of H, halogen, CN, —N(R⁸)₂, —CON(R⁸)₂,—N(R¹³)COR¹³, —S(O)₂R¹³, C₁-C₃alkyl, C₁-C₃ alkoxy, C₆-C₁₀ aryl, 5-10membered heteroaryl having 1, 2, or 3 heteroatoms independently selectedfrom N, O, and S, and 4-6 membered heterocyclyl having 1, 2, or 3heteroatoms independently selected from N, O, and S.
 19. The compound ofclaim 18, or the pharmaceutically acceptable salt thereof, wherein eachR¹⁵, R¹⁶, R¹⁷, and R¹⁸ is independently selected from the groupconsisting of H, CN, —N(R⁸)₂, and —N(R¹³)COR¹³.
 20. The compound ofclaim 19, or the pharmaceutically acceptable salt thereof, wherein Z isCR⁷.
 21. The compound of claim 1, or the pharmaceutically acceptablesalt thereof, wherein


22. The compound of claim 1, or the pharmaceutically acceptable saltthereof, wherein the compound is of Formula III-Z:


23. The compound of claim 1, or the pharmaceutically acceptable saltthereof, wherein Y is N.
 24. The compound of claim 1, or thepharmaceutically acceptable salt thereof, wherein Z is CR⁷.
 25. Thecompound of claim 1, or the pharmaceutically acceptable salt thereof,wherein


26. The compound of claim 1, or the pharmaceutically acceptable saltthereof, wherein R⁷ is H or CH₃.
 27. The compound of claim 1, or thepharmaceutically acceptable salt thereof, wherein the compound has aFormula IIIa-Z:

wherein L is N or CR¹⁵; M is N or CR¹⁶; Q is N or CR¹⁷; and R is N orCR¹⁸; wherein each R¹⁵, R¹⁶, R¹⁷, and R¹⁸ is independently selected fromthe group consisting of H, halogen, CN, —N(R⁸)₂, —CON(R⁸)₂,—N(R¹³)COR¹³, —S(O)₂R¹³, C₁-C₃ alkyl, C₁-C₃ alkoxy, C₆-C₁₀ aryl, 5-10membered heteroaryl having 1, 2, or 3 heteroatoms independently selectedfrom N, O, and S, and 4-6 membered heterocyclyl having 1, 2, or 3heteroatoms independently selected from N, O, and S.
 28. The compound ofclaim 27, or the pharmaceutically acceptable salt thereof, wherein eachR¹⁵, R¹⁶, R¹⁷, and R¹⁸ is independently selected from the groupconsisting of H, CN, —N(R⁸)₂, and —N(R¹³)COR¹³.
 29. The compound ofclaim 27, or the pharmaceutically acceptable salt thereof, wherein: L isN; M is CR¹⁶; Q is CR¹⁷; and R is CR¹⁸; M is N: L is CR¹⁵, Q is CR¹⁷;and R is CR¹⁸; Q is N: L is CR¹⁵: M is CR¹⁶; and R is CR¹⁸; or R is N: Lis CR¹⁵: M is CR¹⁶; and Q is CR¹⁷.
 30. The compound of claim 27, or thepharmaceutically acceptable salt thereof, wherein R¹⁵, R¹⁶, R¹⁷, and R¹⁸are each H.
 31. The compound of claim 1, or the pharmaceuticallyacceptable salt thereof, wherein A in CR¹.
 32. The compound of claim 1,or the pharmaceutically acceptable salt thereof, wherein each R¹, R²,and R³ is independently H, halogen, C₁-C₃ alkyl, or C₂-C₃ alkynyl,wherein the C₂-C₃ alkynyl is unsubstituted or substituted with 1, 2, or3 R⁹ groups.
 33. The compound of claim 1, or the pharmaceuticallyacceptable salt thereof, wherein both R¹ and R³ are H.
 34. The compoundof claim 1, or the pharmaceutically acceptable salt thereof, wherein R²is H, halogen, CN, —N(R¹³)₂, C₁-C₃ alkoxy, C₁-C₃ alkyl, or C₂-C₃alkynyl, wherein the C₂-C₃ alkynyl is unsubstituted or substituted with1, 2, or 3 R⁹ groups.
 35. The compound of claim 1, or thepharmaceutically acceptable salt thereof, wherein R⁹ is —OH, CH₃, orcyclopropyl.
 36. The compound of claim 1, or the pharmaceuticallyacceptable salt thereof, wherein R² is H, Cl, F, —CH₃, —CN, —NH₂,—SO₂CH₃, OCH₃,


37. The compound of claim 1, or the pharmaceutically acceptable saltthereof, wherein R¹ is H, halogen or C₁-C₃ alkyl.
 38. The compound of aclaim 1, or the pharmaceutically acceptable salt thereof, wherein R¹ isF or Cl and R² is H.
 39. The compound of claim 1, or thepharmaceutically acceptable salt thereof, wherein R¹ is F or Cl; R² isH; and R³ is H or C₁-C₃ alkyl.
 40. The compound of claim 1, or thepharmaceutically acceptable salt thereof, wherein each R¹, R² and R³ isH.
 41. The compound of claim 1, or the pharmaceutically acceptable saltthereof, wherein J is H or C₁-C₃ alkyl.
 42. The compound of claim 1, orthe pharmaceutically acceptable salt thereof, wherein m is 0 or 1; and pis 0, 1, 2, or
 3. 43. The compound of claim 1, or the pharmaceuticallyacceptable salt thereof, wherein m is 0 or 1; p is 0, 1, 2, or 3; R²⁰ isC₁-C₃ alkyl; and each R²¹ is independently a halogen or oxo; or two R²¹groups on same atoms are joined together to form a 3-6 memberedcarbocyclic ring or a 3-6 membered heterocyclic ring.
 44. The compoundof claim 1, or the pharmaceutically acceptable salt thereof, R²⁰ isC₁-C₃ alkyl.
 45. The compound of claim 1, or the pharmaceuticallyacceptable salt thereof, wherein p is 0, 1, or
 2. 46. The compound ofclaim 1, or the pharmaceutically acceptable salt thereof, wherein p is 2and the two R²¹ groups are on same atom and are joined together to forma 3-6 membered carbocyclic ring or a 3-6 membered heterocyclic ring. 47.The compound of claim 1, or the pharmaceutically acceptable saltthereof, wherein p is 1 and R²¹ is oxo.
 48. The compound of claim 1, orthe pharmaceutically acceptable salt thereof, wherein n is 0, 1 or 2.49. The compound of claim 1, or the pharmaceutically acceptable saltthereof, wherein


50. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 51. A pharmaceuticalcomposition comprising the compound of claim 1, or the pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable excipient orcarrier.
 52. A method of inhibiting hematopoietic progenitor kinase 1(HPK1) activity in a subject in need thereof, comprising administeringto the subject a therapeutically effective amount of the compound ofclaim 1, or the pharmaceutically acceptable salt thereof.
 53. A methodof treating a disease or disorder associated with increasedhematopoietic progenitor kinase 1 (HPK1) activity in a subject in needthereof, comprising administering to the subject a therapeuticallyeffective amount of the compound of claim 1, or the pharmaceuticallyacceptable salt thereof.